Management of patients with jaundice

Emergency care and nursing in case of jaundice and hepatic coma

 

1. Peculiarity of the examination of the patients with liver’s diseases

LIVER DISEASES

While there are many causes of liver disease (Table 1), they generally present clinically in a few distinct patterns, usually classified as either hepatocellular or cholestatic (obstructive).

 

 

 

CLINICAL HISTORY

The clinical history should focus on the symptoms of liver disease-their nature, pattern of onset, and progression- and on potential risk factors for liver disease. The symptoms of liver disease include constitutional symptoms such as fatigue, weakness, nausea, poor appetite, and malaise and the more liver-specific symptoms of jaundice, dark urine, light stools, itching, abdominal pain, and bloating. Symptoms can also suggest the presence of cirrhosis, end-stage liver disease, or complications of cirrhosis such as portal hypertension. Generally, the constellation of symptoms and their pattern of onset rather than a specific symptom points to an etiology.

Fatigue is the most common and most characteristic symptom of liver disease. It is variously described as lethargy, weakness, listlessness, malaise, increased need for sleep, lack of stamina, and poor energy.

Nausea occurs with more severe liver disease and may accompany fatigue or be provoked by odors of food or eating fatty foods. Vomiting can occur but is rarely persistent or prominent. Poor appetite with weight loss occurs commonly in acute liver diseases but is rare in chronic disease, except when cirrhosis is present and advanced. Diarrhea is uncommon in liver disease, except with severe jaundice, in which case lack of bile acids reaching the intestine can lead to steatorrhea.

Right upper quadrant discomfort or ache (“liver pain”) occurs in many liver diseases and is usually marked by tenderness over the liver area.

Itching occurs with acute liver disease, appearing early in obstructive jaundice (from biliary obstruction or drug-induced cholestasis) and somewhat later in hepatocellular disease (acute hepatitis). Itching also occurs in chronic liver diseases, typically the cholestatic forms such as primary biliary cirrhosis and sclerosing cholangitis where it is often the presenting symptom, occurring before the onset of jaundice.

Jaundice is the hallmark symptom of liver disease and perhaps the most reliable marker of severity. Patients usually report darkening of the urine before they notice scleral icterus. Jaundice is rarely detectable with a bilirubin level less than 43 umol/L (2.5 mg/dL). With severe cholestasis there will also be lightening of the color of the stools and steatorrhea. Jaundice without dark urine usually indicates indirect (unconjugated) hyperbilirubinemia and is typical of hemolytic anemia and the genetic disorders of bilirubin conjugation, the common and benign form being Gilbert’s syndrome and the rare and severe form being Crigler-Najjar syndrome. Gilbert’s syndrome affects up to 5% of the population; the jaundice is more noticeable after fasting and with stress.

Major risk factors for liver disease that should be sought in the clinical history include details of alcohol use, medications (including herbal compounds, birth control pills, and over-the-counter medications), personal habits, sexual activity, travel, exposure to jaundiced or other high-risk persons, injection drug use, recent surgery, remote or recent transfusion with blood and blood products, occupation, accidental exposure to blood or needlestick, and familial history of liver disease.

For assessing the risk of viral hepatitis, a careful history of sexual activity is of particular importance and should include life-time number of sexual partners and, for men, a history of having sex with men. Sexual exposure is a common mode of spread of hepatitis B but is rare for hepatitis C. Maternal-infant transmission occurs with both hepatitis B and C.

Family history can be helpful in assessing liver disease. Familial causes of liver disease include Wilson’s disease; hemochromatosis and a1-antitrypsin (a1AT) deficiency; and the more uncommon inherited pediatric liver diseases of familial intrahepatic cholestasis (FIC), benign recurrent intrahepatic cholestasis (BRIC), and Alagille’s syndrome. Onset of severe liver disease in childhood or adolescence with a family history of liver disease or neuropsychiatric disturbance should lead to investigation for Wilson’s disease. A family history of cirrhosis, diabetes, or endocrine failure and the appearance of liver disease in adulthood should suggest hemochromatosis and lead to investigation of iron status. Patients with abnormal iron studies warrant genotyping of the HFE gene for the C282Y and H63D mutations typical of genetic hemochromatosis. A family history of emphysema should provoke investigation of a1AT levels and, if low, for Pi genotype.

PHYSICAL EXAMINATION

The physical examination rarely demonstrates evidence of liver dysfunction in a patient without symptoms or laboratory findings, nor are most signs of liver disease specific to one diagnosis. Thus, the physical examination usually complements rather than replaces the need for other diagnostic approaches. In many patients, the physical examination is normal unless the disease is acute or severe and advanced. Nevertheless, the physical examination is important in that it can be the first evidence for the presence of hepatic failure, portal hypertension, and liver decompensation. In addition, the physical examination can reveal signs that point to a specific diagnosis, either in risk factors or in associated diseases or findings.

Typical physical findings in liver disease are icterus, hepatomegaly, hepatic tenderness, splenomegaly, spider angiomata, palmar erythema, and excoriations. Signs of advanced disease include muscle-wasting, ascites, edema, dilated abdominal veins, hepatic fetor, asterixis, mental confusion, stupor, and coma.

Icterus is best appreciated by inspecting the sclera under natural light. In fair-skinned individuals, a yellow color of the skin may be obvious.

Spider angiomata and palmar erythema occur in both acute and chronic liver disease and may be especially prominent in persons with cirrhosis, but they can occur in normal individuals and are frequently present during pregnancy. Spider angiomata are superficial, tortuous arterioles and, unlike simple telangiectases, typically fill from the center outwards. Spider angiomata occur only on the arms, face, and upper torso; they can be pulsatile and may be difficult to detect in dark-skinned individuals.

Hepatomegaly is not a very reliable sign of liver disease, because of the variability of the size and shape of the liver and the physical impediments to assessing liver size by percussion and palpation. Marked hepatomegaly is typical of cirrhosis, venoocclusive disease, metastatic or primary cancers of the liver, and alcoholic hepatitis.

Splenomegaly occurs in many medical conditions but can be a subtle but significant physical finding in liver disease. The availability of ultrasound (US) assessment of the spleen allows for confirmation of the physical finding.

Signs of advanced liver disease include muscle-wasting and weight loss as well as hepatomegaly, bruising, ascites, and edema.

Hepatic failure is defined as the occurrence of signs or symptoms of hepatic encephalopathy in a person with severe acute or chronic liver disease. The first signs of hepatic encephalopathy can be subtle and nonspecificѕchange in sleep patterns, change in personality, irritability, and mental dullness. Thereafter, confusion, disorientation, stupor, and eventually coma supervene. Physical findings include asterixis and flapping tremors of the body and tongue. Fetor hepaticus refers to the slightly sweet, ammoniacal odor that is common in patients with liver failure, particularly if there is portal-venous shunting of blood around the liver. Other causes of coma and confusion should be excluded, mainly electrolyte imbalances, sedative use, and renal or respiratory failure.

Several skin disorders and changes occur commonly in liver disease.

2. Laboratory testing and diagnostic liver’s diseases.

LABORATORY TESTING

Diagnosis in liver disease is greatly aided by the availability of reliable and sensitive tests of liver injury and function. A typical battery of blood tests used for initial assessment of liver disease includes measuring levels of serum alanine and aspartate aminotransferases (ALT and AST), alkaline phosphatase, direct and total serum bilirubin, and albumin and assessing prothrombin time. The pattern of abnormalities generally points to hepatocellular versus cholestatic liver disease and will help to decide whether the disease is acute or chronic and whether cirrhosis and hepatic failure are present. Based on these results, further testing over time may be necessary. Other laboratory tests may be helpful, such as g-glutamyl transpeptidase (GGT) to define whether alkaline phosphatase elevations are due to liver disease; hepatitis serology to define the type of viral hepatitis; and autoimmune markers to diagnose primary biliary cirrhosis (antimitochondrial antibody; AMA), sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody; pANCA), autoimmune hepatitis (antinuclear, smooth-muscle, and liver-kidney microsomal antibody). Laboratory Tests. When the physician encounters a patient with unexplained jaundice, there are a battery of tests that are helpful in the initial evaluation. These include total and direct serum bilirubin with fractionation, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests. Enzyme tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase] are helpful in differentiating between a hepatocellular process and a cholestatic process, a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a disproportionate rise in the aminotransferases compared to the alkaline phosphatase. Patients with a cholestatic process have a disproportionate rise in the alkaline phosphatase compared to the aminotransferases. The bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two.

In addition to the enzyme tests, all jaundiced patients should have additional blood tests, specifically an albumin and a prothrombin time, to assess liver function. A low albumin suggests a chronic process such as cirrhosis or cancer. A normal albumin is suggestive of a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.

The results of the bilirubin, enzyme, albumin, and prothrombin time tests will usually indicate whether a jaundiced patient has a hepatocellular or a cholestatic disease. The causes and evaluation of each of these is quite different.

Hepatocellular Conditions  Hepatocellular diseases that can cause jaundice include viral hepatitis, drug or environmental toxicity, alcohol, and end-stage cirrhosis from any cause (Table 3).

 

 

 

 

Cholestatic Conditions  When the pattern of the liver tests suggests a cholestatic disorder, the next step is to determine whether it is intra- or extrahepatic cholestasis. Distinguishing intrahepatic from extrahepatic cholestasis may be difficult. History, physical examination, and laboratory tests are ofteot helpful. The next appropriate test is an ultrasound. The ultrasound is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intra- and extrahepatic biliary tree with a high degree of sensitivity and specificity. The absence of biliary dilatation suggests intrahepatic cholestasis, while the presence of biliary dilatation indicates extrahepatic cholestasis. False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis (PSC) where scarring prevents the intrahepatic ducts from dilating.

In patients with apparent intrahepatic cholestasis, the diagnosis is often made by serologic testing in combination with percutaneous liver biopsy.  The list of possible causes of intrahepatic cholestasis is long and varied (Table 4).  A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. Both hepatitis B and C can cause a cholestatic hepatitis (fibrosing cholestatic hepatitis) that has histologic features that mimic large duct obstruction. This disease variant has been reported in patients who have undergone solid organ transplantation. Hepatitis A, alcoholic hepatitis, EBV, and CMV may also present as cholestatic liver disease.

 

 

 

 

TESTS THAT MEASURE BIOSYNTHETIC FUNCTION OF THE LIVER

Serum Albumin  Serum albumin is synthesized exclusively by hepatocytes. Serum albumin has a long half-life: 15 to 20 days, with approximately 4% degraded per day. Because of this slow turnover, the serum albumin is not a good indicator of acute or mild hepatic dysfunction; only minimal changes in the serum albumin are seen in acute liver conditions such as viral hepatitis, drug-related hepatoxicity, and obstructive jaundice. In hepatitis, albumin levels below 3 g/dL should raise the possibility of chronic liver disease. Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and usually reflects severe liver damage and decreased albumin synthesis. One exception is the patient with ascites in whom synthesis may be normal or even increased, but levels are low because of the increased volume of distribution. However, hypoalbuminemia is not specific for liver disease and may occur in protein malnutrition of any cause, as well as protein-losing enteropathies, nephrotic syndrome, and chronic infections that are associated with prolonged increases in serum interleukin-1 and/or tumor necrosis factor levels that inhibit albumin synthesis. Serum albumin should not be measured for screening in patients in whom there is no suspicion of liver disease. A general medical clinic study of consecutive patients in whom no indications were present for albumin measurement showed that while 12% of patients had abnormal test results, the finding was of clinical importance in only 0.4%.

Serum Globulins  Serum globulins are a group of proteins made up of gamma globulins (immunoglobulins) produced by B lymphocytes and alpha and beta globulins produced primarily in hepatocytes. Gamma globulins are increased in chronic liver disease, such as chronic hepatitis and cirrhosis. In cirrhosis, the increased serum gamma globulin concentration is due to the increased synthesis of antibodies, some of which are directed against intestinal bacteria. This occurs because the cirrhotic liver fails to clear bacterial antigens that normally reach the liver through the hepatic circulation.

Increases in the concentration of specific isotypes of gamma globulins are often helpful in the recognition of certain chronic liver diseases. Diffuse polyclonal increases in IgG levels are common in autoimmune hepatitis; increases greater than 100% should alert the clinician to this possibility. Increases in the IgM levels are common in primary biliary cirrhosis, while increases in the IgA levels occur in alcoholic liver disease.

Coagulation Factors  With the exception of factor VIII, the blood clotting factors are made exclusively in hepatocytes. Their serum half-lives are much shorter than albumin, ranging from 6 hours for factor VII to 5 days for fibrinogen. Because of their rapid turnover, measurement of the clotting factors is the single best acute measure of hepatic synthetic function and helpful in both the diagnosis and assessing the prognosis of acute parenchymal liver disease. Useful for this purpose is the serum prothrombin time, which collectively measures factors II, V, VII, and X. Biosynthesis of factors II, VII, IX, and X depends on vitamin K. The prothrombin time may be elevated in hepatitis and cirrhosis as well as in disorders that lead to vitamin K deficiency such as obstructive jaundice or fat malabsorption of any kind. Marked prolongation of the prothrombin time, >5 s above control and not corrected by parenteral vitamin K administration, is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases.

Diagnosis in liver disease is greatly aided by the availability of reliable and sensitive tests of liver injury and function. A typical battery of blood tests used for initial assessment of liver disease includes measuring levels of serum alanine and aspartate aminotransferases (ALT and AST), alkaline phosphatase, direct and total serum bilirubin, and albumin and assessing prothrombin time. The pattern of abnormalities generally points to hepatocellular versus cholestatic liver disease and will help to decide whether the disease is acute or chronic and whether cirrhosis and hepatic failure are present. Based on these results, further testing over time may be necessary. Other laboratory tests may be helpful, such as g-glutamyl transpeptidase (GGT) to define whether alkaline phosphatase elevations are due to liver disease; hepatitis serology to define the type of viral hepatitis; and autoimmune markers to diagnose primary biliary cirrhosis (antimitochondrial antibody; AMA), sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody; pANCA), autoimmune hepatitis (antinuclear, smooth-muscle, and liver-kidney microsomal antibody).

DIAGNOSTIC IMAGING

There have been great advances made in hepatic imaging, although no method is suitably accurate in demonstrating underlying cirrhosis. There are many modalities available for imaging the liver. US, computed tomography (CT), and magnetic resonance imaging (MRI) are the most commonly employed and are complementary to each other. In general, US and CT have a high sensitivity for detecting biliary duct dilatation and are the first-line options for investigating the patient with suspected obstructive jaundice. Both US and CT can detect a fatty liver, which appears bright on both studies. Endoscopic retrograde cholangiopancreatography (ERCP) is the procedure of choice for visualization of the biliary tree. ERCP also provides several therapeutic options in patients with obstructive jaundice, such as sphincterotomy, stone extraction, and placement of nasobiliary catheters and biliary stents. Doppler US and MRI are used to assess hepatic vasculature and hemodynamics and to monitor surgically or radiologically placed vascular shunts such as transjugular intrahepatic portosystemic shunts (TIPS). CT and MRI are indicated for the identification and evaluation of hepatic masses, staging of liver tumors, and preoperative assessment. With regard to mass lesions, sensitivity of hepatic imaging continues to increase; unfortunately, specificity remains a problem, and often two and sometimes three studies are needed before a diagnosis can be reached. Finally, interventional radiologic techniques allow the biopsy of solitary lesions, insertion of drains into hepatic abscesses, and creation of vascular shunts in patients with portal hypertension. Which modality to use depends on factors such as availability, cost, and experience of the radiologist with each technique.

 

Video: liver ultrasound appearance in chronic hepatitis

 

LIVER BIOPSY

 

 

 

 

 

 

Liver biopsy remains the gold standard in the evaluation of patients with liver disease, particularly in patients with chronic liver diseases. In selected instances, liver biopsy is necessary for diagnosis but is more often useful in assessing the severity (grade) and stage of liver damage, in predicting prognosis, and in monitoring response to treatment.

Diagnosis of Liver Disease. The most common causes of acute liver disease are viral hepatitis (particularly hepatitis A, B, and C), drug-induced liver injury, cholangitis, and alcoholic liver disease. Liver biopsy is usually not needed in the diagnosis and management of acute liver disease, exceptions being situations where the diagnosis remains unclear despite thorough clinical and laboratory investigation. Liver biopsy can be helpful in the diagnosis of drug-induced liver disease and in establishing the diagnosis of acute alcoholic hepatitis.

The most common causes of chronic liver disease in general order of frequency are chronic hepatitis C, alcoholic liver disease, nonalcoholic steatohepatitis, chronic hepatitis B, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, and Wilson’s disease. Strict diagnostic criteria have not been developed for most liver diseases, but liver biopsy plays an important role in the diagnosis of autoimmune hepatitis, primary biliary cirrhosis, nonalcoholic and alcoholic steatohepatitis, and Wilson’s disease (with a quantitative hepatic copper level).

Grading and Staging of Liver Disease. Grading refers to an assessment of the severity or activity of liver disease, whether acute or chronic; active or inactive; and mild, moderate, or severe. Liver biopsy is the most accurate means of assessing severity, particularly in chronic liver disease. Serum aminotransferase levels are used as a convenient and noninvasive means to follow disease activity, but aminotransferases are not always reliable in reflecting disease severity. Thus, normal serum aminotransferases in patients with hepatitis B surface antigen (HBsAg) in serum may indicate the inactive HBsAg carrier state or may reflect mild chronic hepatitis B or hepatitis B with fluctuating disease activity. Serum testing for hepatitis B e antigen and hepatitis B virus DNA can help resolve these different patterns, but these markers can also fluctuate and change over time. Similarly, in chronic hepatitis C, serum aminotransferases can be normal despite moderate activity of disease. Finally, in both alcoholic and nonalcoholic steatohepatitis, aminotransferases are quite unreliable in reflecting severity. In these conditions, liver biopsy is helpful in guiding management and recommending therapy, particularly if therapy is difficult, prolonged, and expensive as is often the case in chronic viral hepatitis. There are several well-verified numerical scales for grading activity in chronic liver disease, the most common being the histology activity index and the Ishak histology scale.

Liver biopsy is also the most accurate means of assessing stage of disease as early or advanced, precirrhotic, and cirrhotic. Staging of disease pertains largely to chronic liver diseases in which progression to cirrhosis and end-stage liver disease can occur, but which may require years or decades to develop. Clinical features, biochemical tests, and hepatic imaging studies are helpful in assessing stage but generally become abnormal only in the middle to late stages of cirrhosis. Early stages of cirrhosis are generally detectable only by liver biopsy. In assessing stage, the degree of fibrosis is usually used as its quantitative measure. The amount of fibrosis is generally staged on a 0 to 4+ (histology activity index) or 0 to 6+ scale (Ishak scale).

Cirrhosis can also be staged clinically. A reliable staging system is the modified Child-Pugh classification with a scoring system of 5 to 15: scores of 5 and 6 being Child-Pugh class A (consistent with “compensated cirrhosis”), scores of 7 to 9 indicating class B, and 10 to 15 class C (Table 2).

 

 

 

 

Thus, liver biopsy is helpful not only in diagnosis but also in management of chronic liver disease and assessment of prognosis. Because liver biopsy is an invasive procedure and not without complications, it should be used only when it will contribute materially to management and therapeutic decisions.

Several biochemical tests are useful in the evaluation and management of patients with hepatic dysfunction. These tests can be used to

 (1) detect the presence of liver disease;

(2) distinguish among different types of liver disorders;

(3) gauge the extent of known liver damage; and

(4) follow the response to treatment.

Liver tests have shortcomings. They can be normal in patients with serious liver disease and abnormal in patients with diseases that do not affect the liver. Liver tests rarely suggest a specific diagnosis; rather, they suggest a general category of liver disease, such as hepatocellular or cholestatic, which then further directs the evaluation.

No one test enables the clinician to accurately assess the liver’s total functional capacity. To increase both the sensitivity and the specificity of laboratory tests in the detection of liver disease, it is best to use them as a battery. Those tests usually employed in clinical practice include the bilirubin, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests. When more than one of these tests provide abnormal findings, or the findings are persistently abnormal on serial determinations, the probability of liver disease is high. When all test results are normal, the probability of missing occult liver disease is low.

When evaluating patients with liver disorders, it is helpful to group these tests into general categories.

TESTS THAT MEASURE BIOSYNTHETIC FUNCTION OF THE LIVER

Serum Albumin. Serum albumin is synthesized exclusively by hepatocytes. Serum albumin has a long half-life: 15 to 20 days, with approximately 4% degraded per day. Because of this slow turnover, the serum albumin is not a good indicator of acute or mild hepatic dysfunction; only minimal changes in the serum albumin are seen in acute liver conditions such as viral hepatitis, drug-related hepatoxicity, and obstructive jaundice. In hepatitis, albumin levels below 3 g/dL should raise the possibility of chronic liver disease. Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and usually reflects severe liver damage and decreased albumin synthesis. One exception is the patient with ascites in whom synthesis may be normal or even increased, but levels are low because of the increased volume of distribution. However, hypoalbuminemia is not specific for liver disease and may occur in protein malnutrition of any cause, as well as protein-losing enteropathies, nephrotic syndrome, and chronic infections that are associated with prolonged increases in serum interleukin-1 and/or tumor necrosis factor levels that inhibit albumin synthesis.

Serum Globulins. Serum globulins are a group of proteins made up of gamma globulins (immunoglobulins) produced by B lymphocytes and alpha and beta globulins produced primarily in hepatocytes. Gamma globulins are increased in chronic liver disease, such as chronic hepatitis and cirrhosis. In cirrhosis, the increased serum gamma globulin concentration is due to the increased synthesis of antibodies, some of which are directed against intestinal bacteria. This occurs because the cirrhotic liver fails to clear bacterial antigens that normally reach the liver through the hepatic circulation.

Increases in the concentration of specific isotypes of gamma globulins are often helpful in the recognition of certain chronic liver diseases. Diffuse polyclonal increases in IgG levels are common in autoimmune hepatitis; increases greater than 100% should alert the clinician to this possibility. Increases in the IgM levels are common in primary biliary cirrhosis, while increases in the IgA levels occur in alcoholic liver disease.

Coagulation Factors. With the exception of factor VIII, the blood clotting factors are made exclusively in hepatocytes. Their serum half-lives are much shorter than albumin, ranging from 6 hours for factor VII to 5 days for fibrinogen. Because of their rapid turnover, measurement of the clotting factors is the single best acute measure of hepatic synthetic function and helpful in both the diagnosis and assessing the prognosis of acute parenchymal liver disease. Useful for this purpose is the serum prothrombin time, which collectively measures factors II, V, VII, and X. Biosynthesis of factors II, VII, IX, and X depends on vitamin K. The prothrombin time may be elevated in hepatitis and cirrhosis as well as in disorders that lead to vitamin K deficiency such as obstructive jaundice or fat malabsorption of any kind. Marked prolongation of the prothrombin time, >5 s above control and not corrected by parenteral vitamin K administration, is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases.

OTHER DIAGNOSTIC TESTS

While tests may direct the physician to a category of liver disease, additional radiologic testing and procedures are ofteecessary to make the proper diagnosis. The two most commonly-used ancillary tests are reviewed here.

Percutaneous Liver Biopsy  Percutaneous biopsy of the liver is a safe procedure that can be easily performed at the bedside with local anesthesia. Liver biopsy is of proven value in the following situations: (1) hepatocellular disease of uncertain cause; (2) prolonged hepatitis with the possibility of chronic active hepatitis; (3) unexplained hepatomegaly; (4) unexplained splenomegaly; (5) hepatic filling defects by radiologic imaging; (6) fever of unknown origin; (7) staging of malignant lymphoma. Liver biopsy is most accurate in disorders causing diffuse changes throughout the liver and is subject to sampling error in focal infiltrative disorders such as hepatic metastases. Liver biopsy should not be the initial procedure in the diagnosis of cholestasis. The biliary tree should first be assessed for signs of obstruction.

Ultrasonography  Ultrasonography is the first diagnostic test to use in patients whose liver tests suggest cholestasis, to look for the presence of a dilated intrahepatic or extrahepatic biliary tree, or to identify gallstones. In addition, it shows space-occupying lesions within the liver, enables the clinician to distinguish between cystic and solid masses, and helps direct percutaneous biopsies. Ultrasound with Doppler imaging can detect the patency of the portal vein, hepatic artery, and hepatic veins and determine the direction of blood flow. This is the first test ordered in patients suspected of having Budd-Chiari syndrome.

3. Criteria for diagnosis of alcoholic fatty liver.

CLINICAL FEATURES

The clinical manifestations of alcoholic fatty liver are subtle and characteristically detected as a consequence of the patient’s visit for a seemingly unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally, patients with fatty liver present with right upper quadrant discomfort, tender hepatomegaly, nausea, and jaundice. Differentiation of alcoholic fatty liver from non-alcoholic fatty liver is difficult unless an accurate drinking history is verified. Alcoholism does not respect social and economic class. In every instance where liver disease is present, a thoughtful and sensitive drinking history should be obtained. Alcoholic hepatitis is associated with a wide gamut of clinical features. Fever, spider nevi, jaundice, and abdominal pain simulating an acute abdomen represent the extreme end of the spectrum; but many patients are entirely asymptomatic. Recognition of the clinical features of alcoholic hepatitis is central to the initiation of an effective and appropriate diagnostic and therapeutic strategy.

LABORATORY FEATURES

Patients with alcoholic fatty liver are often identified through routine screening tests. The typical laboratory abnormalities are nonspecific and include modest elevations of the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) accompanied by hypertriglyceridemia, hypercholesterolemia, and, occasionally, hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of fatty liver, the AST and ALT are usually elevated two- to sevenfold. They rarely are above 400 IU, and the AST/ALT ratio is >1.

Hyperbilirubinemia is common and is accompanied by modest increases in the alkaline phosphatase. Derangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liver injury. The mean corpuscular volume (MCV) and uric acid level are commonly elevated in chronic alcohol abuse. Measurement of the carbohydrate-deficient transferrin (CDT) is superior to the measurement of the gamma-glutamyl transpeptidase (GGTP) or MCV in identifying excessive drinking. Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intra-abdominal collaterals indicates serious liver injury with less potential for complete reversal of liver disease.

4. Criteria for diagnosis of the drugs-toxic hepatitis.

 Liver injury may follow the inhalation, ingestion, or parenteral administration of a number of pharmacologic and chemical agents. These include industrial toxins (e.g., carbon tetrachloride, trichloroethylene, and yellow phosphorus), the heat-stable toxic bicyclic octapeptides of certain species of Amanita and Galerina (hepatotoxic mushroom poisoning), and, more commonly, pharmacologic agents used in medical therapy. It is essential that any patient presenting with jaundice or altered biochemical liver tests be questioned carefully about exposure to chemicals used in work or at home and drugs taken by prescription or bought “over the counter.” Hepatotoxic drugs can injure the hepatocyte directly, e.g., via a free-radical or metabolic intermediate that causes peroxidation of membrane lipids and that results in liver cell injury. Alternatively, the drug or its metabolite can distort cell membranes or other cellular molecules or block biochemical pathways or cellular integrity. Such injuries, in turn, may lead to necrosis of hepatocytes; injure bile ducts, producing cholestasis; or block pathways of lipid movement, inhibit protein synthesis, or impair mitochondrial oxidation of fatty acids, resulting in fat accumulation (steatosis). In general, two major types of chemical hepatotoxicity have been recognized: (1) direct toxic type and (2) idiosyncratic type.

Most drugs, which are water-insoluble, undergo a series of metabolic transformation steps, culminating in a water-soluble form appropriate for renal or biliary excretion. This process begins with oxidation or methylation initially mediated by the mixed-function oxygenases cytochrome P450 (phase I reaction), followed by glucuronidation or sulfation (phase II reaction) or inactivation by glutathione. Most drug hepatotoxicity is mediated by a phase I toxic metabolite, but glutathione depletion, precluding inactivation of harmful compounds by glutathione S-transferase, can contribute as well.

Direct toxic hepatitis occurs with predictable regularity in individuals exposed to the offending agent and is dose-dependent. The latent period between exposure and liver injury is usually short (often several hours), although clinical manifestations may be delayed for 24 to 48 h. Agents producing toxic hepatitis are generally systemic poisons or are converted in the liver to toxic metabolites. The direct hepatotoxins result in morphologic abnormalities that are reasonably characteristic and reproducible for each toxin.

In idiosyncratic drug reactions the occurrence of hepatitis is usually infrequent and unpredictable, the response is not dose-dependent, and it may occur at any time during or shortly after exposure to the drug. Extrahepatic manifestations of hypersensitivity, such as rash, arthralgias, fever, leukocytosis, and eosinophilia, occur in about one-quarter of patients with idiosyncratic hepatotoxic drug reactions; this observation and the unpredictability of idiosyncratic drug hepatotoxicity contributed to the hypothesis that this category of drug reactions is immunologically mediated.

Idiosyncratic reactions lead to a morphologic pattern that is more variable than those produced by direct toxins; a single agent is often capable of causing a variety of lesions, although certain patterns tend to predominate. Depending on the agent involved, idiosyncratic hepatitis may result in a clinical and morphologic picture indistinguishable from that of viral hepatitis (e.g., halothane) or may simulate extrahepatic bile duct obstruction clinically with morphologic evidence of cholestasis. Drug-induced cholestasis ranges from mild to increasingly severe: (1) bland cholestasis with limited hepatocellular injury (e.g., estrogens, 17, a-substituted androgens); (2) inflammatory cholestasis (e.g., phenothiazines, amoxicillin-clavulanic acid, oxacillin, erythromcyin estolate); (3) sclerosing cholangitis (e.g., after intrahepatic infusion of the chemotherapeutic agent floxuridine for hepatic metastases from a primary colonic carcinoma); (4) disappearance of bile ducts, “ductopenic” cholestasis, similar to that observed in chronic rejection following liver transplantation (e.g., carbamazine, chlorpromazine, tricyclic antidepressant agents). Morphologic alterations may also include bridging hepatic necrosis (e.g., methyldopa), or, infrequently, hepatic granulomas (e.g., sulfonamides). Some drugs result in macrovesicular or microvesicular steatosis or steatohepatitis, which in some cases has been linked to mitochondrial dysfunciton and lipid peroxidation. Severe hepatotoxicity associated with steatohepatitis, most likely a result of mitochondrial toxicity, is being recognized with increasing frequency among patients receiving antiretroviral therapy with reverse transcriptase inhibitors (e.g., zidovudine, didanosine) or protease inhibitors (e.g., indinavir, ritonavir) for HIV infection.

Not all adverse hepatic drug reactions can be classified as either toxic or idiosyncratic in type. For example, oral contraceptives, which combine estrogenic and progestational compounds, may result in impairment of hepatic tests and occasionally in jaundice. However, they do not produce necrosis or fatty change, manifestations of hypersensitivity are generally absent, and susceptibility to the development of oral contraceptive-induced cholestasis appears to be genetically determined. Other instances of genetically determined drug hepatotoxicity have been identified. For example, approximately 10% of the population have an autosomally recessive trait associated with the absence of cytochrome P450 enzyme 2D6 and have impaired debrisoquine-4-hydroxylase enzyme activity. As a result, they cannot metabolize, and are at increased risk of hepatotoxicity resulting from, certain compounds such as desipramine, propranolol.

 Classification of the chronic hepatitis. Criteria for diagnosis of the chronic autoimmune hepatitis.

 

CLASSIFICATION OF CHRONIC HEPATITIS

Classification of chronic hepatitis is based upon (1) its cause, (2) its histologic activity, or grade, and (3) its degree of progression, or stage. Thus, neither clinical features alone nor histologic features-requiring liver biopsy–alone are sufficient to characterize and distinguish among the several categories of chronic hepatitis.

Classification by Cause. Clinical and serologic features allow the establishment of a diagnosis of chronic viral hepatitis, caused by hepatitis B, hepatitis B plus D, hepatitis C, or potentially other unknown viruses; autoimmune hepatitis, including several subcategories, types 1, 2, and 3, based on serologic distinctions; drug-associated chronic hepatitis; and a category of unknown cause, or cryptogenic chronic hepatitis (Table 1).

 

 

 

 

Classification by Grade. Grade, a histologic assessment of necroinflammatory activity, is based upon examination of the liver biopsy. An assessment of important histologic features includes the degree of periportal necrosis and the disruption of the limiting plate of periportal hepatocytes by inflammatory cells (so-called piecemeal necrosis or interface hepatitis); the degree of confluent necrosis that links or forms bridges between vascular structures-between portal tract and portal tract or even more important bridges between portal tract and central vein-referred to as bridging necrosis; the degree of hepatocyte degeneration and focal necrosis within the lobule; and the degree of portal inflammation. Several scoring systems that take these histologic features into account have been devised, and the most popular is the numerical histologic activity index (HAI), based on the work of Knodell and Ishak.

 

 Histopathology 

 

• Histology for chronic hepatitis is varied
• Mildest: significant inflammation in portal tracts only, with lots of macrophages, lymphocytes (i.e. immune cells of a chronic nature) with well preserved liver architecture.
• Severe: bridging necrosis, i.e. portal tracts “bridged” by necrotic bands.  deposition of fibrous tissue first only near portal tracts and then eventually periportal with bridging fibrosis.

 

 

 

Classification by Stage. The stage of chronic hepatitis, which reflects the level of progression of the disease, is based on the degree of fibrosis. When fibrosis is so extensive that fibrous septa surround parenchymal nodules and alter the normal architecture of the liver lobule, the histologic lesion is defined as cirrhosis. Staging is based on the degree of fibrosis as follows:

0 = no fibrosis; 1 = mild fibrosis; 2 = moderate fibrosis; 3 = severe fibrosis, including bridging fibrosis; 4 = cirrhosis

Chronic active hepatitis is characterized clinically by continuing hepatic necrosis, portal/periportal and, to a lesser extent, lobular inflammation, and fibrosis. Varying in severity from mild to severe, chronic active hepatitis was recognized to be a progressive disorder that can lead to cirrhosis, liver failure, and death. Morphologic characteristics of chronic active hepatitis include (1) a dense mononuclear infiltrate of the portal tracts, which are substantially expanded into the liver lobule (in the autoimmune type, plasma cells represent a component of the infiltrate); (2) destruction of the hepatocytes at the periphery of the lobule, with erosion of the limiting plate of hepatocytes surrounding the portal triads (piecemeal necrosis or interface hepatitis); (3) connective tissue septa surrounding portal tracts and extending from the portal zones into the lobule, isolating parenchymal cells into clusters and enveloping bile ducts; and (4) evidence of hepatocellular regeneration “rosette” formation, thickened liver cell plates, and regenerative “pseudolobules.” This process may be patchy, with individual liver lobules spared, or it may be diffuse. Histologic evidence of single-cell coagulative necrosis, Councilman or acidophilic bodies, appear in the periportal areas. Piecemeal necrosis is the minimal histologic requirement to establish a diagnosis of chronic active hepatitis, but this change is seen even in mild, relatively nonprogressive forms of chronic active hepatitis. A more severe lesion, bridging hepatic necrosis (originally termed subacute hepatic necrosis), characterizes a more severe and progressive form of chronic active hepatitis. Although bridging necrosis can be seen occasionally in patients with acute hepatitis, in whom it carries no prognostic importance, in chronic active hepatitis this lesion is associated with progression to cirrhosis. Bridging necrosis is characterized by hepatocellular dropout that spans lobules (i.e., between portal tractsѕthe periphery of the lobule-or between portal tracts and central veinsѕthe centrizonal part of the lobule). Collapse of the reticulietwork is a hallmark of bridging necrosis, and bridging fibrosis follows, leading ultimately to architectural reorganization by nodular regeneration, i.e., cirrhosis. A more extensive and ominous variant of bridging necrosis is multilobular collapse, in which bridging necrosis is widespread throughout the liver and which is associated clinically with rapid deterioration and even acute liver failure.

Although progression to cirrhosis is difficult to demonstrate in patients with chronic active hepatitis who have isolated piecemeal necrosis, in more severe forms of chronic active hepatitis, progression to cirrhosis is common. Ordinarily, chronic active hepatitis is more severe clinically than chronic persistent and lobular hepatitis. Although a sizable proportion of patients with chronic active hepatitis are asymptomatic, the majority tend to have mild to severe constitutional symptoms, especially fatigue. Generally, physical findings associated with chronic liver disease and portal hypertension are more common, aminotransferase levels tend to be higher, and jaundice and hyperbilirubinemia are more frequent in this form of chronic hepatitis.

In the new nomenclature for chronic hepatitis, what used to be called chronic active hepatitis spans the entire spectrum of activity grade from minimal, to mild, to severe chronic hepatitis, based on the degree of periportal and piecemeal necrosis, on the degree of lobular inflammation and injury, and on the degree of portal inflammation. Similarly, stage in chronic active hepatitis can translate to mild, moderate, or severe fibrosis as well as to cirrhosis.

AUTOIMMUNE HEPATITIS

Definition. Autoimmune hepatitis (formerly called autoimmune chronic active hepatitis) is a chronic disorder characterized by continuing hepatocellular necrosis and inflammation, usually with fibrosis, which tends to progress to cirrhosis and liver failure. The prominence of extrahepatic features of autoimmunity as well as seroimmunologic abnormalities in this disorder supports an autoimmune process in its pathogenesis; this concept is reflected in the labels “lupoid,” plasma cell, or autoimmune hepatitis.

Immunopathogenesis  The weight of evidence suggests that the progressive liver injury in patients with idiopathic/autoimmune hepatitis is the result of a cell-mediated immunologic attack directed against liver cells; in all likelihood, predisposition to autoimmunity is inherited, while the liver specificity of this injury is triggered by environmental (e.g., chemical or viral) factors. For example, patients have been described in whom apparently self-limited cases of acute hepatitis A or B led to autoimmune hepatitis, presumably because of genetic susceptibility or predisposition. Evidence to support an autoimmune pathogenesis in this type of hepatitis includes the following: (1) In the liver, the histopathologic lesions are composed predominantly of cytotoxic T cells and plasma cells; (2) circulating autoantibodies (nuclear, smooth muscle, thyroid, etc.), rheumatoid factor, and hyperglobulinemia are common; (3) other autoimmune disorders-such as thyroiditis, rheumatoid arthritis, autoimmune hemolytic anemia, ulcerative colitis, proliferative glomerulonephritis, juvenile diabetes mellitus, and Sjogren’s syndromeѕoccur with increased frequency in patients who have autoimmune hepatitis and in their relatives; (4) histocompatibility haplotypes associated with autoimmune diseases, such as HLA-B1, -B8, -DR3, and -DR4, are common in patients with autoimmune hepatitis; and (5) this type of chronic hepatitis is responsive to glucocorticoid/immunosuppressive therapy, effective in a variety of autoimmune disorders.

Cellular immune mechanisms appear to be important in the pathogenesis of autoimmune hepatitis. In vitro studies have suggested that in patients with this disorder, lymphocytes are capable of becoming sensitized to hepatocyte membrane proteins and of destroying liver cells. Abnormalities of immunoregulatory control over cytotoxic lymphocytes (impaired suppressor cell influences) may play a role as well. Studies of genetic predisposition to autoimmune hepatitis demonstrate that certain haplotypes are associated with the disorder. The precise triggering factors, genetic influences, and cytotoxic and immunoregulatory mechanisms involved in this type of liver injury remain poorly defined.

Intriguing clues into the pathogenesis of autoimmune hepatitis come from the observation that circulating autoantibodies are prevalent in patients with this disorder. Among the autoantibodies described in these patients are antibodies to nuclei [so-called antinuclear antibodies (ANA), primarily in a homogeneous pattern] and smooth muscle (so-called anti-smooth-muscle antibodies, directed at actin), anti-LKM, antibodies to “soluble liver antigen” (directed at a member of the glutathione S-transferase gene family), as well as antibodies to the liver-specific asialoglycoprotein receptor (or “hepatic lectin”) and other hepatocyte membrane proteins. Although some of these provide helpful diagnostic markers, their involvement in the pathogenesis of autoimmune hepatitis has not been established.

Humoral immune mechanisms have been shown to play a role in the extrahepatic manifestations of autoimmune/idiopathic hepatitis. Arthralgias, arthritis, cutaneous vasculitis, and glomerulonephritis occurring in patients with autoimmune hepatitis appear to be mediated by the deposition in affected tissue vessels of circulating immune complexes, followed by complement activation, inflammation, and tissue injury. While specific viral antigen-antibody complexes can be identified in acute and chronic viral hepatitis, the nature of the immune complexes in autoimmune hepatitis has not been defined.

Many of the clinical features of autoimmune hepatitis are similar to those described for chronic viral hepatitis. The onset of disease may be insidious or abrupt; the disease may present initially like, and be confused with, acute viral hepatitis; a history of recurrent bouts of what had been labeled acute hepatitis is not uncommon. A subset of patients with autoimmune hepatitis has distinct features. Such patients are predominantly young to middle-aged women with marked hyperglobulinemia and high-titer circulating ANA. This is the group with positive LE preparations (initially labeled “lupoid” hepatitis) in whom other autoimmune features are common. Fatigue, malaise, anorexia, amenorrhea, acne, arthralgias, and jaundice are common. Occasionally, arthritis, maculopapular eruptions (including cutaneous vasculitis), erythema nodosum, colitis, pleurisy, pericarditis, anemia, azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia) occur. In some patients, complications of cirrhosis, such as ascites and edema (associated with hypoalbuminemia), encephalopathy, hypersplenism, coagulopathy, or variceal bleeding may bring the patient to initial medical attention.

The course of autoimmune hepatitis may be variable. In those with mild disease or limited histologic lesions (e.g., piecemeal necrosis without bridging), progression to cirrhosis is limited. In those with severe symptomatic autoimmune hepatitis (aminotransferase levels >10 times normal, marked hyperglobulinemia, “aggressive” histologic lesionsѕbridging necrosis or multilobular collapse, cirrhosis), the 6-month mortality without therapy may be as high as 40%. Such severe disease accounts for only 20% of cases; the natural history of milder disease is variable, often accentuated by spontaneous remissions and exacerbations. Especially poor prognostic signs include multilobular collapse at the time of initial presentation and failure of the bilirubin to improve after 2 weeks of therapy. Death may result from hepatic failure, hepatic coma, other complications of cirrhosis (e.g., variceal hemorrhage), and intercurrent infection. In patients with established cirrhosis, hepatocellular carcinoma may be a late complication.

Laboratory features of autoimmune hepatitis are similar to those seen in chronic viral hepatitis. Liver biochemical tests are invariably abnormal but may not correlate with the clinical severity or histopathologic features in individual cases. Many patients with autoimmune hepatitis have normal serum bilirubin, alkaline phosphatase, and globulin levels with only minimal aminotransferase elevations. Serum AST and ALT levels are increased and fluctuate in the range of 100 to 1000 units. In severe cases, the serum bilirubin level is moderately elevated [51 to 171 umol/L (3 to 10 mg/dL)]. Hypoalbuminemia occurs in patients with very active or advanced disease. Serum alkaline phosphatase levels may be moderately elevated or near normal. In a small proportion of patients, marked elevations of alkaline phosphatase activity occur; in such patients, clinical and laboratory features overlap with those of primary biliary cirrhosis. The prothrombin time is often prolonged, particularly late in the disease or during active phases.

Hypergammaglobulinemia (>2.5 g/dL) is common in autoimmune hepatitis. Rheumatoid factor is common as well. Circulating autoantibodies are also common. The most characteristic are ANA in a homogeneous staining pattern. Smooth-muscle antibodies are less specific, seen just as frequently in chronic viral hepatitis. Because of the high levels of globulins achieved in the circulation of some patients with autoimmune hepatitis, occasionally the globulins may bind nonspecifically in solid-phase binding immunoassays for viral antibodies. This has been recognized most commonly in tests for antibodies to hepatitis C virus. In fact, studies of autoantibodies in autoimmune hepatitis have led to the recognition of new categories of autoimmune hepatitis. Type I autoimmune hepatitis is the classic syndrome occurring in young women, associated with marked hyperglobulinemia, lupoid features, and circulating ANA. Type II autoimmune hepatitis, often seen in children and more common in Mediterranean populations, is associated not with ANA but with anti-LKM. Actually, anti-LKM represent a heterogeneous group of antibodies. In type II autoimmune hepatitis, the antibody is anti-LKM1, directed against P450 IID6. This is the same anti-LKM seen in some patients with chronic hepatitis C. Anti-LKM2 is seen in drug-induced hepatitis, and anti-LKM3 is seen in patients with chronic hepatitis D. Type II autoimmune hepatitis has been subdivided by some authorities into two categories, one more typically autoimmune and the other associated with viral hepatitis type C. Autoimmune hepatitis type IIa is felt to be autoimmune, is more likely to occur in young women, is associated with hyperglobulinemia, is associated with high-titer anti-LKM1, responds to glucocorticoid therapy. Type IIb autoimmune hepatitis is associated with hepatitis C virus infection, tends to occur in older men, is associated with normal globulin levels and low-titer anti-LKM1, responds to interferon, and occurs most commonly in Mediterranean countries. In addition, another type of autoimmune hepatitis has been recognized, autoimmune hepatitis type III. These patients lack ANA and anti-LKM1 and have circulating antibodies to soluble liver antigen, which are directed at hepatocyte cytoplasmic cytokeratins 8 and 18. Most of these patients are women and have clinical features similar to those of patients with type I autoimmune hepatitis.

 Chronic viral hepatitis.

Chronic Hepatitis B. The likelihood of chronicity after acute hepatitis B varies as a function of age. Infection at birth is associated with a clinically silent acute infection but a 90% chance of chronic infection, while infection in young adulthood in immunocompetent persons is typically associated with clinically apparent acute hepatitis but a risk of chronicity of only approximately 1%. Most cases of chronic hepatitis B among adults, however, occur in patients who never had a recognized episode of clinically apparent acute viral hepatitis. The degree of liver injury (grade) in patients with chronic hepatitis B is variable, ranging from none in asymptomatic carriers, to mild, to severe. Among adults with chronic hepatitis B, histologic features are of prognostic importance. In one long-term study of patients with chronic hepatitis B, investigators found a 5-year survival of 97% for patients with chronic persistent hepatitis (mild chronic hepatitis), of 86% for patients with chronic active hepatitis (moderate to severe chronic hepatitis), and of only 55% for patients with chronic active hepatitis and postnecrotic cirrhosis. Probably more important to consider than histology alone in patients with chronic hepatitis B is the degree of hepatitis B virus (HBV) replication. Chronic hepatitis B can be divided into two phases based on the relative level of HBV replication. The relatively replicative phase is characterized by the presence in the serum of markers of HBV replication [hepatitis B e antigen (HBeAg) HBV DNA], by the presence in the liver of detectable intrahepatocyte nucleocapsid antigens [primarily hepatitis B core antigen (HBcAg)], by high infectivity, and by accompanying liver injury; HBV DNA can be detected in the liver but is extrachromosomal. In contrast, the relatively nonreplicative phase is characterized by the absence of conventional markers of HBV replication (HBeAg and HBV DNA detectable by hybridization) but an association with anti-HBe, the absence of intrahepatocytic HBcAg, limited infectivity, and minimal liver injury; HBV DNA can be detected in the liver but is integrated into the host genome. Those in the replicative phase tend to have more severe chronic hepatitis, while those in the nonreplicative phase tend to have minimal or mild chronic hepatitis or to be asymptomatic hepatitis B carriers; however, distinctions in HBV replication and in histologic category do not always coincide. The likelihood of converting spontaneously from relatively replicative to nonreplicative chronic HBV infection is approximately 10 to 15% per year. The conversion from replicative to nonreplicative chronic hepatitis B is associated with a transient elevation in aminotransferase activity resembling acute hepatitis; occasionally, spontaneous resumptions of replicative activity occur ionreplicative infection; and occasionally, HBV variants occur in which serologic markers of replication (HBeAg) are absent, despite the presence of replicative infection. Chronic HBV infection, especially when acquired at birth or in early childhood, is associated with an increased risk of hepatocellular carcinoma.

The spectrum of clinical features of chronic hepatitis B is broad, ranging from asymptomatic infection to debilitating disease or even end-stage, fatal hepatic failure. The onset of the disease tends to be insidious in most patients, with the exception of the very few in whom chronic disease follows failure of resolution of clinically apparent acute hepatitis B. Fatigue is a common symptom, and persistent or intermittent jaundice is a common feature in severe or advanced cases. Intermittent deepening of jaundice and recurrence of malaise and anorexia, as well as worsening fatigue, are reminiscent of acute hepatitis; such exacerbations may occur spontaneously, often coinciding with evidence of virologic reactivation, may lead to progressive liver injury, and, when superimposed on well-established cirrhosis, may cause hepatic decompensation. Complications of cirrhosis occur in end-stage chronic hepatitis and include ascites, edema, bleeding gastroesophageal varices, hepatic encephalopathy, coagulopathy, or hypersplenism. Occasionally, these complications bring the patient to initial clinical attention. Extrahepatic complications of chronic hepatitis B, similar to those seen during the prodromal phase of acute hepatitis B, are associated with deposition of circulating hepatitis B antigen-antibody immune complexes. These include arthralgias and arthritis, which are common, and the more rare purpuric cutaneous lesions (leukocytoclastic vasculitis), immune-complex glomerulonephritis, and generalized vasculitis (polyarteritis nodosa).

Laboratory features of chronic hepatitis B do not distinguish adequately between histologically mild and severe hepatitis. Aminotransferase elevations tend to be modest for chronic hepatitis B but may fluctuate in the range of 100 to 1000 units. As is true for acute viral hepatitis B, alanine aminotransferase (ALT, or SGPT) tends to be more elevated than aspartate aminotransferase (AST, or SGOT); however, once cirrhosis is established, AST tends to exceed ALT. Levels of alkaline phosphatase activity tend to be normal or only marginally elevated. In severe cases, moderate elevations in serum bilirubin [51.3 to 171 umol/L (3 to 10 mg/dL)] occur. Hypoalbuminemia and prolongation of the prothrombin time occur in severe or end-stage cases. Hyperglobulinemia and detectable circulating autoantibodies are distinctly absent in chronic hepatitis B (in contrast to autoimmune hepatitis).

Chronic Hepatitis D (Delta Hepatitis)  Chronic hepatitis D may follow acute coinfection with HBV but at a rate no higher than the rate of chronicity of hepatitis B. That is, although HDV coinfection can increase the severity of acute hepatitis B, HDV does not increase the likelihood of progression to chronic hepatitis B. However, when HDV superinfection occurs in a person who is already chronically infected with HBV, long-term HDV infection is the rule and a worsening of the liver disease the expected consequence. Except for severity, chronic hepatitis B plus D has similar clinical and laboratory features to those seen in chronic hepatitis B alone. Relatively severe chronic hepatitis, with or without cirrhosis, is the rule, and mild chronic hepatitis the exception. A distinguishing serologic feature of chronic hepatitis D is the presence in the circulation of antibodies to liver-kidney microsomes (anti-LKM); however, the anti-LKM seen in hepatitis D are designated anti-LKM3, are directed against uridine diphosphate glucuronosyltransferase, and are distinct from anti-LKM1 seen in patients with autoimmune hepatitis and in a subset of patients with chronic hepatitis C.

Chronic Hepatitis C. Regardless of the epidemiologic mode of acquisition of hepatitis C virus (HCV) infection, chronic hepatitis follows acute hepatitis C in 50 to 70% of cases; even in those with a return to normal in aminotransferase levels after acute hepatitis C, chronic infection is common, adding up to an 85 to 90% likelihood of chronic HCV infection after acute hepatitis C. Furthermore, in patients with chronic transfusion-associated hepatitis followed for 10 to 20 years, progression to cirrhosis occurs in about 20%. Such is the case even for patients with relatively clinically mild chronic hepatitis, including those without symptoms, with only modest elevations of aminotransferase activity, and with mild chronic hepatitis on liver biopsy. Even in cohorts of well-compensated patients with chronic hepatitis C (no complications of chronic liver disease and with normal hepatic synthetic function), the prevalence of cirrhosis may be as high as 50%. Many cases of hepatitis C are identified in asymptomatic patients who have no history of acute hepatitis C, e.g., those discovered while attempting to donate blood or as a result of routine laboratory screening tests. The source of HCV infection in most of these cases is not defined, although a long-forgotten percutaneous exposure in the remote past can be elicited in a substantial proportion. The natural history of chronic hepatitis C identified under these circumstances remains to be determined.

Despite this substantial rate of progression of chronic hepatitis C, and despite the fact that liver failure can result from end-stage chronic hepatitis C, the long-term prognosis for chronic hepatitis C in a majority of patients is relatively benign. Mortality over 10 to 20 years among patients with transfusion-associated chronic hepatitis C has been showot to differ from mortality in a matched population of transfused patients in whom hepatitis C did not develop. Although death in the hepatitis group is more likely to result from liver failure, and although hepatic decompensation may occur in approximately 15% of such patients over the course of a decade, the majority (almost 60%) of patients remain asymptomatic and well compensated, with no clinical sequelae of chronic liver disease. Overall, then, chronic hepatitis C tends to be very slowly and insidiously progressive, if at all, in the vast majority of patients, while in approximately a quarter of cases, chronic hepatitis C will progress eventually to end-stage cirrhosis. Referral bias may account for the more severe outcomes described in cohorts of patients reported from tertiary-care centers versus the more benign outcomes in cohorts of patients monitored from initial blood-product-associated acute hepatitis. Still unexplained, however, are the wide ranges in reported progression to cirrhosis, from 2% over 17 years in a population of women with hepatitis C infection acquired from contaminated anti-D immune globulin to 30% over Ј11 years in recipients of contaminated intravenous immune globulin.

Progression of liver disease in patients with chronic hepatitis C has been reported to be more likely in patients with older age, longer duration of infection, advanced histologic stage and grade, genotype 1 (especially type 1b), more complex quasispecies diversity, and increased hepatic iron. Among these variables, however, duration of infection appears to be the most important, and many of the others probably reflect disease duration to some extent (e.g., quasispecies diversity, hepatic iron accumulation).

Perhaps the best prognostic indicator in chronic hepatitis C is liver histology. Patients with mild necrosis and inflammation as well as those with limited fibrosis have an excellent prognosis and limited progression to cirrhosis. In contrast, among patients with moderate to severe necroinflammatory activity or fibrosis, including septal or bridging fibrosis, progression to cirrhosis is highly likely over the course of 10 to 20 years. Among patients with compensated cirrhosis associated with hepatitis C, the 10-year survival is close to 80 percent; mortality occurs at a rate of 2 to 6% per year, decompensation at a rate of 4 to 5% per year, and hepatocellular carcinoma at a rate of 1 to 3% per year.

In addition, severity of chronic hepatitis is greater and progression of chronic liver disease is more accelerated in patients who have chronic hepatitis C as well as other liver processes, including alcoholic liver disease, chronic hepatitis B, hemochromatosis, and a1-antitrypsin deficiency. No other epidemiologic or clinical features of chronic hepatitis C (e.g., severity of acute hepatitis, level of aminotransferase activity, level of HCV RNA, presence or absence of jaundice) are predictive of eventual outcome. Despite the relative benignity of chronic hepatitis C over time, cirrhosis following chronic hepatitis C has been associated with the late development, after several decades, of hepatocellular carcinoma (HCC). The annual rate of HCC in cirrhotic patients with hepatitis C is 1 to 3%.

 

 

Clinical features of chronic hepatitis C are similar to those for chronic hepatitis B. Generally, fatigue is the most common symptom; jaundice is rare. Immune-complex mediated extrahepatic complications of chronic hepatitis C are less common than in chronic hepatitis B, with the exception of essential mixed cryoglobulinemia. This is the case despite the fact that assays for immune-complex-like activity are often positive in patients with chronic hepatitis C. In addition, chronic hepatitis C has been associated with extrahepatic complications unrelated to immune-complex injury. These include Sjogren’s syndrome, lichen planus, and porphyria cutanea tarda. Laboratory features of chronic hepatitis C are similar to those in patients with chronic hepatitis B, but aminotransferase levels tend to fluctuate more (the characteristic episodic pattern of aminotransferase activity) and to be lower, especially in patients with long-standing disease. An interesting and occasionally confusing finding in patients with chronic hepatitis C is the presence of autoantibodies. Rarely, patients with autoimmune hepatitis and hyperglobulinemia have false-positive enzyme immunoassays for anti-HCV. On the other hand, some patients with serologically confirmable chronic hepatitis C have circulating anti-LKM. These antibodies are anti-LKM1, as seen in patients with autoimmune hepatitis type2, and are directed against a 33-amino-acid sequence of P450 IID6. The occurrence of anti-LKM1 in some patients with chronic hepatitis C may result from the partial sequence homology between the epitope recognized by anti-LKM1 and two segments of the HCV polyprotein. In addition, the presence of this autoantibody in some patients with chronic hepatitis C suggests that autoimmunity may be playing a role in the pathogenesis of chronic hepatitis C.

 

 

7. Classification of the cirrhosis. Criteria for diagnosis of posthepatitic cirrhosis

 

 

 

 

 

 

 

 

 

 

POSTHEPATITIC AND CRYPTOGENIC CIRRHOSIS

Posthepatitic or postnecrotic cirrhosis represents the final common pathway of many types of chronic liver disease. Coarsely nodular and multilobular cirrhosis are terms synonymous with posthepatitic cirrhosis. The term cryptogenic cirrhosis has been used interchangeably with postpathepatitic 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).

Etiology  Posthepatitic cirrhosis is a morphologic term referring to a defined stage of advanced chronic liver injury of both specific and unknown (cryptogenic) causes. Epidemiologic and serologic evidence suggest that viral hepatitis (hepatitis B or hepatitis C) may be an antecedent factor in from one-fourth to three-fourths of cases of apparently cryptogenic posthepatitic cirrhosis. In areas where hepatitis B virus (HBV) infection is endemic (e.g., Southeast Asia, sub-Saharan Africa), up to 15% of the population may acquire the infection in early childhood, and cirrhosis may ultimately develop in one-fourth of these chronic carriers. Before routine screening of blood donors was introduced, hepatitis C occurred in 5 to 10% of blood recipients. Following infection, cirrhosis may ultimately develop in more than 20% of individuals after 20 years. More than half of patients who would previously have been designated as having cryptogenic chronic liver disease have evidence of HCV infection. Increasing recognition of the progressive nature of nonalcoholic steatohepatitis has revealed that a large portion of cases previously designated cryptogenic cirrhosis may be attributable to this disorder. Posthepatitic cirrhosis may also develop in patients with autoimmune hepatitis.

The most common causes of cirrhosis include chronic HCV infection, alcohol, primary biliary cirrhosis, primary sclerosing cholangitis, and nonalcoholic steatohepatitis (NASH), less common causes of posthepatitic cirrhosis, including drugs and toxins, are listed in Table 2.

 

 

 

 

BILIARY CIRRHOSIS

Biliary cirrhosis results from injury to or prolonged obstruction of either the intrahepatic or extrahepatic biliary system. It is associated with impaired biliary excretion, destruction of hepatic parenchyma, and progressive fibrosis. Primary biliary cirrhosis (PBC) is characterized by chronic inflammation and fibrous obliteration of intrahepatic bile ductules. Secondary biliary cirrhosis (SBC) is the result of long-standing obstruction of the larger extrahepatic ducts. Although primary and secondary biliary cirrhosis are separate pathophysiologic entities with respect to the initial insult, many clinical features are similar.

PRIMARY BILIARY CIRRHOSIS

Etiology and Pathogenesis  The cause of PBC remains unknown. Several observations suggest that a disordered immune response may be involved. PBC is frequently associated with a variety of disorders presumed to be autoimmune iature, 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 more than 90% of patients with PBC and only rarely in other forms of liver disease. It has been demonstrated that these autoantibodies recognize three to five inner mitochondrial membrane proteins identified as enzymes of the pyruvate dehydrogenase complex (PDC), the branched chain-ketoacid dehydrogenase complex (BCKDC), and the a-ketoglutarate dehydrogenase complex (KGDC). The major autoantigen in PBC (found in 90% of patients) has been identified as the 74-kDa E2 component of the PDC, dihydrolipoamide acetyltransferase. The antibodies are directed to a region essential for binding of a lipoic acid cofactor and inhibit the overall enzymatic activity of the PDC. Other AMA autoantibodies in PNC patients are directed to similar constituents of BCKDC and KGDC and also inhibit their enzymatic function. It remains unclear whether these properties have a direct pathogenetic role in the development of PBC. In addition to AMA, elevated serum levels of IgM and cryoproteins consisting of immune complexes capable of activating the alternative complement pathway are found in 80 to 90% of patients. Aberrant expression of major histocompatibility complex class II molecules has been found on biliary epithelium in association with PBC, suggesting that these cells may serve as antigen-presenting cells in this setting. Lymphocytes are prominent in the portal regions and surround damaged bile ducts. These histologic findings resemble those in graft-versus-host disease following bone marrow transplantation and suggest that damage to bile ducts may be immunologically mediated, perhaps reflecting a defect in a suppressor cell population.

Pathology  PBC is divided into four stages based on morphologic findings. The earliest recognizable lesion (stage I), termed chronic nonsuppurative destructive cholangitis, is a necrotizing inflammatory process of the portal triads. It is characterized by destruction of medium and small bile ducts, a dense infiltrate of acute and chronic inflammatory cells, mild fibrosis, and occasionally, bile stasis. At times, periductal granulomas and lymph follicles are found adjacent to affected bile ducts. Subsequently, the inflammatory infiltrate becomes less prominent, the number of bile ducts is reduced, and smaller bile ductules proliferate (stage II). Progression over a period of months to years leads to a decrease in interlobular ducts, loss of liver cells, and expansion of periportal fibrosis into a network of connective tissue scars (stage III). Ultimately, cirrhosis, which may be micronodular or macronodular, develops (stage IV).

Clinical Features

Xanthelasmas in biliary cirrhosis as a result of primary biliary cholangitis

Signs and Symptoms  Many patients with PBC are asymptomatic, and the disease is initially detected on the basis of elevated serum alkaline phosphatase levels during routine screening. The majority of such patients remain asymptomatic for prolonged periods, although most ultimately develop progressive liver injury.

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 excreton. 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. Eventually, signs of hepatocellular failure and portal hypertension develop and ascites appears. Progression may be quite variable. Whereas a proportion of asymptomatic patients may show no signs of progression for a decade or longer, in others, death due to hepatic insufficiency may occur within 5 to 10 years after the first signs of the illness. Such decompensation is often precipitated by uncontrolled variceal hemorrhage or infection.

Physical examination may be entirely normal in the early phase of the disease, when patients are asymptomatic or pruritus is the sole complaint. Later, there may be jaundice of varying intensity, hyperpigmentation of the exposed skin areas, xanthelasmas and tendinous and planar xanthomas, moderate to striking hepatomegaly, splenomegaly, and clubbing of the fingers. Bone tenderness, signs of vertebral compression, ecchymoses, glossitis, and dermatitis may all be noted. Clinical evidence of the sicca syndrome can be found in as many as 75% of patients, and serologic evidence of autoimmune thyroid disease in 25%. Other conditions encountered with increased frequency include rheumatoid arthritis, CREST syndrome, keratoconjunctivitis sicca, IgA deficiency, type 1 diabetes mellitus, scleroderma, pernicious anemia, and renal tubular acidosis. Bone disease is often a significant problem encountered over the course of the disease. While osteomalacia occurs due to diminished vitamin D absorption, accelerated osteoporosis in this patient population (the majority of whom are postmenopausal women) is even more common.

Laboratory Findings  PBC is increasingly diagnosed at a presymptomatic stage, prompted by the finding of a twofold or greater elevation of the serum alkaline phosphatase during routine screening. Serum 5ў-nucleotidase activity and g-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). The latter is both relatively specific and sensitive; a positive test is found in over 90% of symptomatic patients and is present in fewer than 5% of patients with other liver diseases. As the disease evolves, the serum bilirubin level rises progressively and may reach 510 umol/L (30 mg/dL) or more in the final stages. Serum aminotransferase values rarely exceed 2.5 to 3.3 ukat (150 to 200 units). Hyperlipidemia is common, and a striking increase of the serum unesterified cholesterol is ofteoted. An abnormal serum lipoprotein (lipoprotein X) may be present in PBC but is not specific and appears in other cholestatic conditions. A deficiency of bile salts in the intestine leads to moderate steatorrhea and impaired absorption of the fat-soluble vitamins and hypoprothrombinemia. Patients with PBC have elevated liver copper levels, but this finding is not specific and is found in all disorders in which there is prolonged cholestasis.

Diagnosis  PBC should be considered in middle-aged women with unexplained pruritus or an elevated serum alkaline phosphatase and in whom there may be other clinical or laboratory features of protracted impairment of biliary excretion. Although a positive serum AMA determination provides important diagnostic evidence, false-positive results do occur; therefore, liver biopsy should be performed to confirm the diagnosis. Rarely, the AMA test may be negative in patients with histologic features of PBC. Frequently, patients have antibodies to the E2 protein in tests using these specific antigens. In some cases with histologic features of PBC and a negative AMA, antinuclear or smooth-muscle antibodies are present (as in autoimmune hepatitis), and the designation autoimmune cholangitis is applied. The natural history of this entity, however, appears to resemble that of PBC. If the AMA test is negative, the biliary tract should be evaluated to exclude primary sclerosing cholangitis and remediable extrahepatic biliary tract obstruction, especially in view of the frequent presence of coexisting cholelithiasis.

SECONDARY BILIARY CIRRHOSIS

Etiology  SBC results from prolonged partial or total obstruction of the common bile duct or its major branches. In adults, obstruction is most frequently caused by postoperative strictures or gallstones, usually with superimposed infectious cholangitis. Chronic pancreatitis may lead to biliary stricture and secondary cirrhosis. SBC is also an important complication of primary sclerosing cholangitis, a progressive immunologic disorder of the intrahepatic and extrahepatic biliary tree. Patients with malignant tumors of the common bile duct or pancreas rarely survive long enough to develop SBC. In children, congenital biliary atresia and cystic fibrosis are common causes of SBC. Choledochal cysts, if unrecognized, may also be a rare cause of SBC.

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. Extravasation of bile from ruptured interlobular bile ducts into areas of periportal necrosis leads to the formation of “bile lakes” surrounded by cholesterol-rich pseudoxanthomatous cells. As in other forms of cirrhosis, injury is accompanied by regeneration in residual parenchyma. These changes gradually lead to a finely nodular cirrhosis. In general, at least 3 to 12 months is required for biliary obstruction to result in cirrhosis. Relief of the obstruction is frequently accompanied by biochemical and morphologic improvement.

Clinical Features. The symptoms, signs, and biochemical findings of SBC are similar to those of PBC. Jaundice and pruritus are usually the most prominent features. In addition, fever and/or right upper quadrant pain, reflecting bouts of cholangitis or biliary colic, are typical. The manifestations of portal hypertension are found only in advanced cases. SBC should be considered in any patient with clinical and laboratory evidence of prolonged obstruction to bile flow, especially when there is a history of previous biliary tract surgery or gallstones, bouts of ascending cholangitis, or right upper quadrant pain. Cholangiography (either percutaneous or endoscopic) usually demonstrates the underlying pathologic process. Liver biopsy, although not always necessary from a clinical standpoint, can document the development of cirrhosis.

 

 Alcoholic cirrhosis.

 

 

 

 

Alcoholic cirrhosis is only one of many consequences resulting from chronic alcohol ingestion, and it often accompanies other forms of alcohol-induced liver injury, including alcoholic fatty liver and alcoholic hepatitis. Alcoholic cirrhosis, historically referred to as Laennec’s cirrhosis, is the most common type of cirrhosis encountered in North America and many parts of western Europe and South America. It is characterized by diffuse fine scarring, fairly uniform loss of liver cells, and small regenerative nodules, and therefore it is sometimes referred to as micronodular cirrhosis. However, micronodular cirrhosis may also result from other types of liver injury (e.g., following jejunoileal bypass), and thus alcoholic cirrhosis and micronodular cirrhosis are not necessarily synonymous. Conversely, alcoholic cirrhosis may progress to macronodular cirrhosis with time.

Pathology and Pathogenesis  With continued alcohol intake and destruction of hepatocytes, fibroblasts (including activated hepatic stellate cells that have transformed into myofibroblasts with contractile properties) appear at the site of injury and deposit collagen. Weblike septa of connective tissue appear in periportal and pericentral zones and eventually connect portal triads and central veins. This fine connective tissue network surrounds small masses of remaining liver cells, which regenerate and form nodules. Although regeneration occurs within the small remnants of parenchyma, cell loss generally exceeds replacement. With continuing hepatocyte destruction and collagen deposition, the liver shrinks in size, acquires a nodular appearance, and becomes hard as “end-stage” cirrhosis develops. Although alcoholic cirrhosis is usually a progressive disease, appropriate therapy and strict avoidance of alcohol may arrest the disease at most stages and permit functional improvement. In addition, there is strong evidence that concomitant chronic hepatitis C virus (HCV) infection significantly accelerates development of alcoholic cirrhosis.

Clinical Features

Signs and Symptoms. Alcoholic cirrhosis may be clinically silent, and many cases (10 to 40%) are discovered incidentally at laparotomy or autopsy. In many cases symptoms are insidious in onset, occurring usually after 10 or more 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.

 

 

Spider naevus in liver cirrhosis in the ventral side of the
left shoulder

 

 

 

palmar erythema

 

 

 

 

Gynaecomastia in liver cirrhosis

 

 

 

 

 

 

Laboratory Findings.In advanced alcoholic liver disease, abnormalities of laboratory tests are more common. Anemia may result from acute and chronic gastrointestinal blood loss, coexistent nutritional deficiency (notably of folic acid and vitamin B12), hypersplenism, and a direct suppressive effect of alcohol on the bone marrow. Hemolytic anemia, presumably due to effects of hypercholesterolemia or erythrocyte membranes resulting in unusual spurlike projections (acanthocytosis), has been described in some alcoholics with cirrhosis. Mild or pronounced hyperbilirubinemia may be found, usually in association with varying elevations of serum alkaline phosphatase levels. Levels of serum AST (asparate aminotransferase) are frequently elevated, but levels >5ukat (300 units) are unusual and should prompt one to look for other coincident or complicating factors. In contrast to viral hepatitis, the serum AST is usually disproportionately elevated relative to ALT (alanine aminotransferase), i.e., AST/ALT ratio  >2. This discrepancy in alcoholic liver disease may result from the proportionally greater inhibition of ALT synthesis by ethanol, which may be partially reversed by pyridoxal phosphate.

The serum prothrombin time is frequently prolonged, reflecting reduced synthesis of clotting proteins, most notably the vitamin K-dependent factors.

The serum albumin level is usually depressed, while serum globulins are increased. Hypoalbuminemia reflects in part overall impairment in hepatic protein synthesis, while hyperglobulinemia is thought to result from nonspecific stimulation of the reticuloendothelial system. Elevated blood ammonia levels in patients with hepatic encephalopathy reflect diminished hepatic clearance because of impaired liver function and shunting of portal venous blood around the cirrhotic liver into the systemic circulation.

A variety of metabolic disturbances may be detected. Glucose intolerance due to endogenous insulin resistance may be present; however, clinical diabetes is uncommon. Central hyperventilation may lead to respiratory alkalosis in patients with cirrhosis. Dietary deficiency and increased urinary losses lead to hypomagnesemia and hypophosphatemia. In patients with ascites and dilutional hyponatremia, hypokalemia may occur from increased urinary potassium losses due in part to hyperaldosteronism. Prerenal azotemia is also observed in such patients.

Diagnosis  Alcoholic cirrhosis should be strongly suspected in patients with a history of prolonged or excessive alcohol intake and physical signs of chronic liver disease. However, since only 10 to 15% of individuals with excessive alcohol intake develop cirrhosis, other causes and types of liver disease may have to be excluded. The clinical features and laboratory findings are usually sufficient to provide reasonable indication of the presence and extent of hepatic injury. Although a percutaneous needle biopsy of the liver is not usually necessary to confirm the typical findings of alcoholic hepatitis or cirrhosis, it may be helpful in distinguishing patients with less advanced liver disease from those with cirrhosis and in excluding other forms of liver injury such as viral hepatitis. Biopsy may also be helpful as a diagnostic tool in evaluating patients with clinical findings suggestive of alcoholic liver disease who deny alcohol intake. In patients with features of cholestasis, ultrasonography may be appropriate to exclude the presence of extrahepatic biliary obstruction. When the clinical status of an otherwise stable cirrhotic patient deteriorates without an obvious explanation, complicating conditions, such as infection, portal vein thrombosis, and hepatocellular carcinoma, should be sought.

 

 

Treatment of the chronic hepatitis, cirrhosis and their complications.

Treatment of the alcoholic cirrhosis is a serious illness that requires long-term medical supervision and careful management. Therapy of the underlying liver disease is largely supportive. Specific treatment is directed at particular complications such as variceal bleeding and ascites. While some studies suggest that administration of glucocorticoids in moderately large doses for 4 weeks is helpful in patients with severe alcoholic hepatitis and encephalopathy, these drugs have no role in the treatment of established alcoholic cirrhosis. While one study suggested a mortality benefit for the antifibrotic agent colchicine in alcoholic cirrhosis, it has not yet been reproduced; thus colchicine cannot be routinely recommended.

All medicines must be administered with caution in the patient with cirrhosis, especially those eliminated or modified through hepatic metabolism or biliary pathways. In particular, care must be taken to avoid overzealous use of drugs that may directly or indirectly precipitate complications of cirrhosis. For example, vigorous treatment of ascites with diuretics may result in electrolyte abnormalities or hypovolemia, which can lead to coma. Similarly, even modest doses of sedatives can lead to deepening encephalopathy. Aspirin should be avoided in patients with cirrhosis because of its effects on coagulation and gastric mucosa. Acetaminophen should be used with caution and in doses of less than 2 g/day. Patients who drink alcohol are more sensitive to the hepatotoxic effects of acetaminophen, probably due to increased metabolism of the drug to toxic intermediates and decreased glutathione levels.^

Treatment of the posthepatitic cirrhosis.

Management is usually limited to treatment of the complications of portal hypertension, including control of ascites, avoidance of drugs or excessive protein intake that may induce hepatic coma, and prompt treatment of infections. In patients with asymptomatic cirrhosis, expectant management alone is appropriate. In those patients in whom posthepatitic cirrhosis has developed as a result of a treatable condition, therapy directed at the primary disorder may limit further progression (e.g., Wilson’s disease, hemochromatosis).

 

 

MAJOR COMPLICATIONS OF CIRRHOSIS The clinical course of patients with advanced cirrhosis is often complicated by a number of important sequelae that are independent of the etiology of the underlying liver disease. These include portal hypertension and its consequences (e.g., gastroesophageal varices and splenomegaly), ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatocellular carcinoma.

 

PORTAL HYPERTENSION

 

 Definition an

 

 

Postsinusoidal obstruction may also occur outside the liver at the level of the hepatic veins (e.g., Budd-Chiari syndrome), the inferior vena cava, or, less commonly, within the liver (e.g., venocclusive disease). Clinically significant portal hypertension is present in >60% of patients with cirrhosis. Portal vein obstruction is the second most common cause; it may be idiopathic or occur in association with cirrhosis, infection, pancreatitis, or abdominal trauma. Portal vein thrombosis may develop in a variety of hypercoagulable states including polycythemia vera; essential thrombocythemia; deficiencies of protein C, protein S, or antithrombin III; resistance to activated protein C (factor V Leiden); and a mutation of the prothrombin gene (G20210A). Portal vein thrombosis may be idiopathic, though some of these patients may have a subclinical myeloproliferative disorder. Hepatic vein thrombosis (Budd-Chiari syndrome) and hepatic venoocclusive disease are relatively infrequent causes of portal hypertension. Portal vein occlusion may result in massive hematemesis from gastroesophageal varices, but ascites is usually found only when cirrhosis is present.

Clinical Features  The major clinical manifestations of portal hypertension include hemorrhage from gastroesophageal varices, splenomegaly with hypersplenism, ascites, and acute and chronic hepatic encephalopathy. These are related, at least in part, to the development of portal-systemic collateral channels. The absence of valves in the portal venous system facilitates retrograde (hepatofugal) blood flow from the high-pressure portal venous system to the lower-pressure systemic venous circulation. Major sites of collateral flow involve the veins around 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.

Diagnosis. In patients with known liver disease, the development of portal hypertension is usually revealed by the appearance of splenomegaly, ascites, encephalopathy, and/or esophageal varices. Conversely, the finding of any of these features should prompt evaluation of the patient for the presence of underlying portal hypertension and liver disease. Varices are most reliably documented by fiberoptic esophagoscopy; their presence lends indirect support to the diagnosis of portal hypertension.

 

 

 

 

TREATMENT Although treatment is usually directed toward a specific complication of portal hypertension, attempts are sometimes made to reduce the pressure in the portal venous system. Surgical decompression procedures have been used for many years to lower portal pressure in patients with bleeding esophageal varices. However, portal-systemic shunt surgery does not result in improved survival rates in patients with cirrhosis. Decompression caow be accomplished without surgery through the percutaneous placement of a portal-systemic shunt, termed a transjugular intrahepatic portosystemic shunt (TIPS). b-Adrenergic blockade with propranolol or nadolol reduces portal pressure through vasodilatory effects on both the splanchnic arterial bed and the portal venous system in combination with reduced cardiac output. Such therapy has been shown to be effective in preventing both a first variceal bleed and subsequent episodes after an initial bleed. Treatment of patients with clinically significant sequelae of portal hypertension, especially variceal bleeding, with doses of propranolol titrated to reduce the resting pulse by 25% is reasonable if no contraindications exist.

Vigorous treatment of patients with alcoholic hepatitis and cirrhosis, chronic active hepatitis, or other liver diseases may lead to a fall in portal pressure and to a reduction in variceal size. In general, however, portal hypertension due to cirrhosis is not reversible. In appropriately selected patients, hepatic transplantation will be beneficial.

VARICEAL 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. Because patients with varices may bleed just as frequently from other gastrointestinal lesions (e.g., peptic ulcer, gastritis), exclusion of other bleeding sources is important even in patients with prior variceal hemorrhage. Endoscopy is the best approach to evaluate upper gastrointestinal hemorrhage in patients with known or suspected portal hypertension.

TREATMENT. Variceal bleeding is a life-threatening emergency. Prompt estimation and vigorous replacement of blood loss to maintain intravascular volume are essential and take precedence over diagnostic studies and more specific intervention to stop the bleeding. However, excessive fluid administration can increase portal pressure with resultant further bleeding and should therefore be avoided. Replacement of clotting factors with fresh-frozen plasma is important in patients with coagulopathy. Patients are best managed in an intensive care unit and require close monitoring of central venous or pulmonary capillary wedge pressures, urine output, and mental status. Only when the patient is hemodynamically stable should attention be directed toward specific diagnostic studies (especially endoscopy) and other therapeutic modalities to prevent further or recurrent bleeding.

About half of all episodes of variceal hemorrhage cease without intervention, although the risk of rebleeding is very high. The medical management of acute variceal hemorrhage includes the use of vasoconstrictors (somatostatin/octreotide or vasopressin), balloon tamponade, and endoscopic banding of varices or endoscopic sclerosis of varices (sclerotherapy).

Where available, endoscopic intervention should be employed as the first line of treatment to control bleeding acutely. Over the past 18 years, endoscopic sclerosis of esophageal varices has been extensively employed. In this procedure, the varices are injected with one of several sclerosing agents via a needle-tipped catheter passed through the endoscope.

The effectiveness of nonselective b-adrenergic blocking agents (e.g., propranolol) in the management of acute variceal bleeding is limited due to concomitant hypotension resulting from hypovolemia.

Surgical treatment of portal hypertension and variceal bleeding involves the creation of a portal-systemic shunt to permit decompression of the portal system. Two types of portal systemic shunts have been used: nonselective shunts, to decompress the entire portal system, and selective shunts, intended to decompress only the varices while maintaining blood flow to the liver itself.

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. b-Adrenergic blockade with propranolol (reducing splanchnic arterial pressure as well as portal pressure) is sometimes effective in ameliorating this condition. H2 receptor antagonists or other agents useful in the treatment of peptic disease are usually not helpful.

SPLENOMEGALY Congestive splenomegaly is common in patients with severe portal hypertension. Rarely, massive splenomegaly from nonhepatic disease leads to portal hypertension due to increased blood flow in the splenic vein.

Clinical Features. Although usually asymptomatic, splenomegaly may be massive and contribute to the thrombocytopenia or pancytopenia of cirrhosis. In the absence of cirrhosis, splenomegaly in association with variceal hemorrhage should suggest the possibility of splenic vein thrombosis. TREATMENT Splenomegaly usually requires no specific treatment, although massive enlargement of the spleen may occasionally necessitate splenectomy at the time of shunt surgery. However, it should be noted that splenectomy without an accompanying shunt may actually increase portal pressure, and portal vein thrombosis may result from splenectomy. Splenectomy may also be indicated if splenomegaly is the cause rather than the result of portal hypertension (as in splenic vein thrombosis). Thrombcytopenia alone is rarely severe enough to necessitate removal of the spleen. Splenectomy should be avoided in a patient eligible for liver transplantation.

 

                                                                                                                     ASCITES

 

 

 

 

 

 

                                                      

 

 

 

 

 

 

 

 

 

 

 

 

 

Ascites is the accumulation of excess fluid within the peritoneal cavity. It is most frequently encountered in patients with cirrhosis and other forms of severe liver disease, but a number of other disorders may lead to either transudative or exudative ascites. TREATMENT A thorough search should be made for precipitating factors in the patient with recent onset of or worsening ascites, e.g., excessive salt intake, medicatiooncompliance, superimposed infection, worsening liver disease, portal vein thrombosis, or development of hepatocellular carcinoma. When ascites develops in the setting of severe, acute liver disease, resolution of ascites is likely to follow improvement in liver function. More commonly, ascites develops in patients with stable or steadily worsening liver function. Paracentesis should usually be performed with a small-gauge needle at the time of initial evaluation or at the time of any clinical deterioration of a cirrhotic patient with ascites. A small amount of fluid (<200 mL) should be obtained and examined for evidence of infection, tumor, or other possible causes and complications of ascites. Therapeutic intervention is indicated both to prevent potential complications and to control progressive increase in ascites, which may become pronounced enough to cause physical discomfort. For the patient with a modest accumulation, therapy can be undertaken as an outpatient and should be gentle and incremental. The goal is the loss of no more than 1.0 kg/d if both ascites and peripheral edema are present and no more than 0.5 kg/d in patients with ascites alone. In some patients, particularly those with a large accumulation of fluid, it may be desirable to hospitalize the patient so that daily weights and frequent serum electrolyte levels can be monitored and compliance ensured. Although abdominal girth measurements are frequently used as an index of fluid loss, they tend to be unreliable.

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. These agents are also preferred because of their gentle action and specific potassium-sparing properties. Spironolactone is initially given in a dose of 100 mg a day and is increased as needed by 100 mg/d every several days to a maximum dose that should rarely exceed 400 mg/d. 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 levels, reflecting effective competitive inhibition of aldosterone. Conversely, the development of azotemia or hyperkalemia may be dose-limiting or even warrant a reduction in the amount of this medication. In some patients, diuresis cannot be initiated despite maximal doses of distal tubule-acting agents (e.g., 400 mg spironolactone) because of avid proximal tubular sodium absorption. More potent and proximally acting diuretics (furosemide, thiazide, or ethacrynic acid) may then be added cautiously to the regimen. Spironolactone plus furosemide, 40 or 80 mg/d, is usually sufficient to initiate a diuresis in most patients. However, such aggressive therapy must be used with great caution to avoid plasma volume depletion, azotemia, and hypokalemia, which may lead to encephalopathy.

In patients with pronounced ascites, particularly those requiring hospitalization, large-volume paracentesis has proven to be an effective and less costly approach to initial management than prolonged bed rest and conventional diuretic treatment. In this approach, ascitic fluid is removed by peritoneal cannula using strict aseptic techniques and monitoring hemodynamic and renal function. This can be safely accomplished in a single session. The need for concomitant albumin replacement by intravenous infusion remains controversial but may be prudent in the patient without peripheral edema, to avoid depleting the intravascular space and precipitating hypotension. Maintenance diuretic therapy in conjunction with sodium restriction may then be instituted to avoid recurrent ascites.

A minority of patients with advanced cirrhosis has “refractory ascites” or rapidly reaccumulate fluid after control by paracentesis.

HEPATORENAL SYNDROME

Clinical Features and Diagnosis  Worsening azotemia, hyponatremia, progressive oliguria, and hypotension are the hallmarks of the hepatorenal syndrome. This syndrome, which is distinct from prerenal azotemia, may be precipitated by severe gastrointestinal bleeding, sepsis, or overly vigorous attempts at diuresis or paracentesis; it may also occur without an obvious cause. It is essential to exclude other causes of renal impairment often seen in these patients. These include prerenal azotemia or acute tubular necrosis due to hypovolemia (e.g., secondary to gastrointestinal bleeding or diuretic therapy) or an increased nitrogen load such as that seen as a result of bleeding. Drug nephrotoxicity is also often a consideration, particularly in the patient who has received agents such as aminoglycosides or contrast dye. The diagnosis rests on the finding of an elevated serum creatinine level [>133 umol/L (>1.5 g/dL)] that fails to improve with volume expansion or withdrawal of diuretics, together with an unremarkable urine sediment. The diagnosis is supported by the demonstration of avid urinary sodium retention. Typically, the urine sodium concentration is <5 mmol/L, a concentration lower than that generally found in uncomplicated prerenal azotemia. TREATMENT Treatment is usually unsuccessful. Although some patients with hypotension and decreased plasma volume may respond to infusions of salt-poor albumin, volume expansion must be undertaken with caution to avoid precipitating variceal bleeding. Vasodilator therapy, including intravenous infusions of low dose dopamine, is not effective. While TIPS has been reported to improve renal function in some patients, its use caot be recommended. In appropriate candidates, the treatment of choice for hepatorenal syndrome is liver transplantation.

HEPATIC ENCEPHALOPATHY

Hepatic (portal-systemic) encephalopathy is a complex neuropsychiatric syndrome characterized by disturbances in consciousness and behavior, personality changes, fluctuating neurologic signs, asterixis or “flapping tremor,” and distinctive electroencephalographic changes. Encephalopathy may be acute and reversible or chronic and progressive. In severe cases, irreversible coma and death may occur. Acute episodes may recur with variable frequency.

In the patient with otherwise stable cirrhosis, hepatic encephalopathy often follows a clearly identifiable precipitating event.

Hepatic encephalopathy has protean manifestations, and any neurologic abnormality, including focal deficits, may be encountered. In patients with acute encephalopathy, neurologic deficits are completely reversible upon correction of underlying precipitating factors and/or improvement in liver function, but in patients with chronic encephalopathy, the deficits may be irreversible and progressive. Cerebral edema is frequently present and contributes to the clinical picture and overall mortality in patients with both acute and chronic encephalopathy.

The diagnosis of hepatic encephalopathy should be considered when four major factors are present: (1) acute or chronic hepatocellular disease and/or extensive portal-systemic collateral shunts (the latter may be either spontaneous, e.g., secondary to portal hypertension, or surgically created, e.g., portacaval anastomosis); (2) disturbances of awareness and mentation, which may progress from forgetfulness and confusion to stupor and finally coma; (3) shifting combinations of neurologic signs, including asterixis, rigidity, hyperreflexia, extensor plantar signs, and rarely, seizures; and (4) a characteristic (but nonspecific) symmetric, high-voltage, triphasic slow-wave (2 to 5 per second) pattern on the electroencephalogram. Asterixis (“liver flap,” “flapping tremor”) is a nonrhythmic asymmetric lapse in voluntary sustained position of the extremities, head, and trunk. It is best demonstrated by having the patient extend the arms and dorsiflex the hands. Because elicitation of asterixis depends on sustained voluntary muscle contraction, it is not present in the comatose patient. Asterixis is nonspecific and also occurs in patients with other forms of metabolic brain disease. 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.

Grading or classifying the stages of hepatic encephalopathy is often helpful in following the course of the illness and assessing response to therapy.

The diagnosis of hepatic encephalopathy is usually one of exclusion. There are no diagnostic liver function test abnormalities, although an elevated serum ammonia level in the appropriate clinical setting is highly suggestive of the diagnosis. Examination of the cerebrospinal fluid is unremarkable, and computed tomography of the brain shows no characteristic abnormalities until late in stage IV when cerebral edema may supervene. A number of conditions, particularly disorders related to acute and chronic alcoholism, can mimic the clinical features of hepatic encephalopathy. These include acute alcohol intoxication, sedative overdose, delirium tremens, Wernicke’s encephalopathy, and Korsakoff’s psychosis. Subdural hematoma, meningitis, and hypoglycemia or other metabolic encephalopathies must also be considered, especially in patients with alcoholic cirrhosis. In young patients with liver disease and neurologic abnormalities, Wilson’s disease should be excluded. TREATMENT Early recognition and prompt treatment of hepatic encephalopathy are essential. Patients with acute, severe hepatic encephalopathy (stage IV) require the usual supportive measures for the comatose patient. Specific treatment of hepatic encephalopathy is aimed at (1) elimination or treatment of precipitating factors and (2) lowering of blood ammonia (and other toxin) levels by decreasing the absorption of protein and nitrogenous products from the intestine. In the setting of acute gastrointestinal bleeding, blood in the bowel should be promptly evacuated with laxatives (and enemas if necessary) in order to reduce the nitrogen load. Protein should be excluded from the diet, and constipation should be avoided. Ammonia absorption can be decreased by the administration of lactulose, a nonabsorbable disaccharide that acts as an osmotic laxative. Metabolism of lactulose by colonic bacteria may also result in an acid pH that favors conversion of ammonia to the poorly absorbed ammonium ion. In addition, lactulose may actually diminish ammonia production through its direct effects on bacterial metabolism. 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. 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). 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. The use of agents such as levodopa, bromocriptine, keto analogues of essential amino acids, and intravenous amino acid formulations rich in branched-chain amino acids in the treatment of acute hepatic encephalopathy remains of unproven benefit. 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.

Chronic encephalopathy may be effectively controlled by administration of lactulose. Management of patients with chronic encephalopathy should include dietary protein restriction (usually to 60 g/d) in combination with low doses of lactulose or neomycin. Nephrotoxicity or ototoxicity may be limiting in prolonged usage of neomycin. There are suggestions that vegetable protein may be preferable to animal protein.

TREATMENT OF THE HEPATITIS

Management of chronic hepatitis B depends on the level of virus replication. Although progression to cirrhosis is more likely in severe chronic than in mild or moderate chronic hepatitis B, all forms of chronic viral hepatitis can be progressive. Interferon a (IFN-a) was the first approved therapy for chronic hepatitis B, but the recently approved dideoxynucleoside lamivudine expands the options for treatment. The most common indication for treatment is chronic “replicative” hepatitis B, with detectable HBeAg and HBV DNA (by hybridization assay), elevated ALT activity, and histologic evidence of chronic hepatitis on liver biopsy in an immunocompetent adult. A 16-week course of INF-a given by subcutaneous injection at a daily dose of 5 million units, or three times a week at a dose of 10 million units, results in seroconversion from “replicative” (detectable HBeAg and HBV DNA) to “nonreplicative” (undetectable HBeAg and HBV DNA by hybridization assay) HBV infection in approximately 35% of patients, with a concomitant improvement in liver histologic features. As a result of INF-a therapy, approximately 20% of patients acquire anti-HBe, and in early trials, approximately 8% lost hepatitis B surface antigen (HBsAg). Successful interferon therapy and seroconversion is often accompanied by an acute hepatitis-like elevation in aminotransferase activity, which has been postulated to result from enhanced cytolytic T cell clearance of HBV-infected hepatocytes. Relapse after successful therapy is rare (1 or 2%). The likelihood of responding to interferon is higher in patients with lower levels of HBV DNA and substantial elevations of ALT. Although children can respond as well as adults, interferon therapy has not been effective in very young children infected at birth. Similarly, interferon therapy has not been effective in immunosuppressed persons, Asian patients with minimal-to-mild ALT elevations, patients with pre-core mutant HBV infection, or in patients with decompensated chronic hepatitis B (in whom such therapy can actually be detrimental, sometimes precipitating decompensation, often associated with severe adverse effects). Among patients with HBeAg loss during therapy, long-term follow-up has demonstrated that 80% experience eventual loss of HBsAg, i.e., all serologic markers of infection, and normalization of ALT over a 9-year posttreatment period. In addition, improved long-term and complication-free survival as well as a reduction in the frequency of hepatocellular carcinoma have been documented among interferon responders, supporting the conclusion that successful interferon therapy improves the natural history of chronic hepatitis B.

Complications of interferon therapy include systemic “flulike” symptoms, marrow suppression, emotional lability (irritability commonly, depression rarely), autoimmune reactions (especially autoimmune thyroiditis), and miscellaneous side effects such as alopecia, rashes, diarrhea, and numbness and tingling of the extremities. With the possible exception of autoimmune thyroiditis, all these side effects are reversible upon dose lowering or cessation of therapy.

In patients with chronic hepatitis B, long-term therapy with glucocorticoids is not only ineffective but also detrimental. Short-term glucocorticoid therapy, however, has been advocated as a potential antiviral approach. Glucocorticoids increase HBV replication and expression in hepatocytes and depress cytolytic T cells. When glucocorticoids are administered for a brief time and then withdrawn abruptly, cytolytic T cells, suppressed while HBV replication was enhanced by the drug, resume their presteroid function. These restored cytolytic T cells attack hepatocytes, the HBV expression of which had been enhanced by the brief pulse of glucocorticoid therapy. An acute hepatitis-like flare of aminotransferase activity follows and may be accompanied by a dramatic drop, or even loss of, HBV replication. Such glucocorticoid “priming” prior to interferon therapy has not been shown to be more effective than interferon alone and has been abandoned.

Several nucleoside analogues active against HBV are being evaluated and developed. Famciclovir and ganciclovir have only limited activity against hepatitis B; however, lamivudine, which inhibits reverse transcriptase activity of both HIV and HBV, is a potent and effective agent for patients with chronic hepatitis B. Lamivudine suppresses HBV DNA by a median of four orders of magnitude at oral daily doses of 100 mg. In clinical trials conducted in Asia, North America, Europe, and Australia, lamivudine therapy for 12 months was associated with almost universal suppression of HBV DNA detectable by hybridization assays; loss of HBeAg in 32 to 33%; HBeAg seroconversion (i.e., conversion from HBeAg-reactive to anti-HBe-reactive) in 16 to 20%; normalization of ALT in approximately 40%; improvement in histology in over 50%; and retardation in fibrosis in 20%. Among patients who experienced HBeAg responses during therapy, 70 to 80% maintained the response over longer than a year of follow-up monitoring. Because maintenance of the response to lamivudine occurs in almost all patients with an HBeAg response, the achievement of an HBeAg response may be a viable stopping point in therapy. If HBeAg is unaffected by lamivudine therapy, the current approach is to continue therapy until an HBeAg response occurs, but long-term therapy may be required to suppress HBV replication and, in turn, limit liver injury. Preliminary observations indicate that HBeAg seroconversions can increase to a level of 27% after 2 years and 44% after 3 years of therapy.

Losses of HBsAg have been few during lamivudine therapy, and this observation had been cited as an advantage of interferon over lamivudine; however, in head-to-head comparisons between interferon and lamivudine monotherapy, HBsAg losses were rare in both groups. Trials in which lamivudine and interferon were administered in combination failed to show a benefit of combination therapy over lamivudine monotherapy for either treatment-naive patients or prior interferoonresponders.

Among patients with HBeAg and HBV DNA but with normal ALT activity, lamivudine suppresses liver injury during therapy but rarely achieves an HBeAg response. In patients with pre-core HBV mutations, who lack HBeAg but who have detectable HBV DNA and liver injury, lamivudine suppresses HBV DNA and normalizes ALT in 65% and improves liver histology in 60%. When therapy is discontinued, reactivation is common, and these patients require long-term therapy.

Clinical and laboratory side effects of lamivudine are negligible, indistinguishable from those observed in placebo recipients. During lamivudine therapy, transient ALT elevations, resembling those seen during interferon therapy and during spontaneous HBeAg-to-anti-HBe seroconversions, occur in a quarter of patients. These ALT elevations may result from restored cytolytic T cell activation permitted by suppression of HBV replication. Similar ALT elevations, however, occur at an identical frequency in placebo recipients, but ALT elevations associated with HBeAg seroconversion are confined to lamivudine-treated patients. When therapy is stopped after a year of therapy, 2- to 3-fold ALT elevations occur in 20 to 30% of lamivudine-treated patients, representing renewed liver-cell injury as HBV replication returns. Although these posttreatment flares are almost always transient and mild, rare severe exacerbations have been observed, mandating close and careful clinical and virologic monitoring after discontinuation of treatment.

Long-term monotherapy with lamivudine is associated with methionine-to-valine or methionine-to-isoleucine mutations in the YMDD (tyrosine-methionine-aspartate-aspartate) motif of HBV DNA polymerase, analogous to mutations that occur in patients with HIV infection treated with this drug. During a year of therapy, YMDD mutations occur in 15 to 30% of patients; the frequency increases at year two to 38% and at year three to almost 50%. Although transient elevations in ALT and HBV DNA levels occur when such variants emerge, YMDD-variant HBV appears to be less replicatively competent and a less robust pathogen. Even after YMDD mutations occur, HBV DNA and ALT levels as well as histologic scores tend to remain lower than baseline levels in immunocompetent patients. In immunosuppressed patients, a proportion of patients with YMDD mutations experience hepatic decompensation. Until other antivirals are developed, the approach to YMDD variants emerging during lamivudine treatment is to continue therapy. Other antiviral drugs, such as the experimental agent adefovir dipivoxil, inhibit YMDD-variant HBV. In the future, combination antiviral therapy will almost invariably become the norm as new agents are introduced.

Because lamivudine monotherapy can result universally in the rapid emergence of YMDD variants in persons with HIV infection, patients with chronic hepatitis B should be tested for anti-HIV prior to therapy; if HIV infection is identified, lamivudine monotherapy at the HBV daily dose of 100 mg is contraindicated. These patients should be treated with triple-drug antiretroviral therapy, including a lamivudine daily dose of 300 mg. The safety of lamivudine during pregnancy has not been established.

No treatment is indicated or available for asymptomatic “nonreplicative” hepatitis B carriers. Whereas patients with decompensated chronic hepatitis B are not candidates for interferon therapy, they may respond to lamivudine, with reversal of the signs of decompensation.

Antiviral therapy and lamivudine – drugs are quite comparable in efficacy as first-line therapy for chronic hepatitis B. Interferon requires only brief-duration therapy, too limited in duration to support viral variants, but requires subcutaneous injections and is associated with a high level of intolerability. Lamivudine requires long-term therapy in most patients and, when used alone, fosters the emergence of viral variants. On the other hand, lamivudine is taken orally, is very well tolerated, leads to improved histology even in the absence of HBeAg responses, and is effective even in patients who fail to respond to interferon. Although some prefer to begin with interferon, most physicians and patients prefer lamivudine as first-line therapy.

For patients with end-stage chronic hepatitis B, liver transplantation is the only potential lifesaving intervention. Reinfection of the new liver is almost universal; however, the likelihood of liver injury associated with hepatitis B in the new liver is variable. The majority of patients become high-level viremic carriers with minimal liver injury. Unfortunately, an unpredictable proportion experience severe hepatitis B-related liver injury, sometimes a fulminant-like hepatitis, sometimes a rapid recapitulation of the original severe chronic hepatitis B. Prevention of recurrent hepatitis B after liver transplantation has been achieved by prophylaxis with hepatitis B immune globulin and with nucleoside analogues such as lamivudine; in addition, nucleoside analogues have been used successfully to reverse posttransplantation liver injury associated with recurrent hepatitis B.

TREATMENT

Two approaches to antiviral therapy of chronic hepatitis C have been approved: monotherapy with interferon and combination therapy with interferon plus ribavirin. According to a National Institutes of Health Consensus Development Conference in March 1997, responses measured at the end of treatment are referred to as end-treatment responses, and responses sustained for at least 6 months after discontinuation of therapy are referred to as sustained responses.

Interferon Monotherapy  Interferon a, administered by subcutaneous injection three times a week for 6 months yields end-treatment biochemical responses (return to normal of ALT levels) as high as approximately 50% and virologic responses (undetectable HCV RNA) by polymerase chain reaction (PCR) of approximately 30%. Unfortunately, because of a relapse rate as high as 90% in end-treatment responders, these responses are not maintained after discontinuation of therapy except in a small minority of patients; after 6 months of interferon monotherapy, the likelihood of a sustained biochemical and virologic response is only approximately 10%. Even in the absence of a biochemical/virologic response, however, end-treatment histologic responsesѕprimarily reductions in periportal and lobular activityѕoccur in three-fourths of treated patients. Unlike the case in hepatitis B, in chronic hepatitis C successful responses to therapy are not accompanied by transient, acute-hepatitis-like elevations in aminotransferase activity; instead, ALT levels fall precipitously. Between 85 to 90% of responses occur within the first 3 months of therapy; responses thereafter are rare.

In a proportion of cases, markers of HCV replication can be eradicated by interferon therapy, and durable responses with normal ALT, improved histology, and absence of HCV RNA in serum and liver have been documented many years after successful therapy. A small proportion of patients, approximately 10%, experience biochemical “breakthrough” during interferon therapy and are classified as nonresponders. In general, they remain refractory to retreatment thereafter; some such breakthroughs are associated with interferon antibodies, while others may reflect mutations in the HCV genome that render HCV nonresponsive to interferon.

Levels of HCV RNA fall in tandem with ALT levels during interferon therapy, but loss of detectable HCV RNA does not preclude relapse. When a patient experiences an apparently sustained biochemical response after discontinuing interferon but continues to remain viremic, as reflected by the persistence of detectable HCV RNA, future biochemical relapse is likely. Patient variables that tend to correlate with sustained responsiveness to interferon include a low baseline level of HCV RNA and histologically mild hepatitis. Patients with cirrhosis can respond, but they are less likely to do so and especially unlikely to have a sustained response. Patients with HCV genotype 1 are less likely to respond than patients with other genotypes. Other variables reported to correlate with increased responsiveness include brief duration of infection, low HCV quasispecies diversity, immunocompetence, and low liver iron levels. High levels of HCV RNA, more histologically advanced liver disease, and high quasispecies diversity all go hand in hand with advanced duration of infection, which may be the single most important variable determining interferon responsiveness. The ironic fact, then, is that patients whose disease is least likely to progress are the ones most likely to respond to interferon and vice versa. Finally, among patients with genotype 1b, responsiveness to interferon is enhanced in those with amino-acid-substitution mutations in the nonstructural protein 5A gene.

The most effective approach to increasing responsiveness to interferon monotherapy is to increase the duration of therapy to 12 months or longer, a regimen associated with a sustained biochemical and virologic response of approximately 20%. Higher doses of interferon (e.g., 5 to 10 million units) or daily injections increase response rates only marginally and at a substantial cost in intolerability. Thus, if interferon monotherapy is selected, the consensus is that 3 million units for at least 12 months is the preferred regimen. Currently, three types of IFN-a are approved in the United States; for the two recombinant products, the recommended dose is 3 million units, and for the one synthetic consensus interferon (synthesized to represent the amino acids at each position that occur most frequently among the multiple, natural interferon a subspecies), the dose is 9ug. Several other types of INF-a, including lymphoblastoid interferon, are available in Europe and Asia. A review of the different types of INF-a during the NIH Consensus Development Conference in 1997 led to the conclusion that they are all equivalent in efficacy.

Studies of viral kinetics have shown that despite a virion half life in serum of only 2 to 3 h, the level of HCV is maintained by a high replication rate of 1012 hepatitis C virions per day. Interferon a blocks virion production or release with an efficacy that increases with increasing drug doses; moreover, the calculated death rate for infected cells during interferon therapy is inversely related to viral load; patients with the most rapid death rate of infected hepatocytes are more likely to achieve undetectable HCV RNA at 3 months; achieving this landmark is predictive of a subsequent sustained response. Therefore, to achieve rapid viral clearance from serum and the liver, high-dose induction therapy has been advocated. In practice, high-dose induction therapy has not yielded higher sustained response rates. Other approaches that have been suggested include tapering therapy slowly, rather than discontinuing therapy abruptly, and, because high liver iron levels are associated with nonresponsiveness, the addition of phlebotomy to interferon therapy. None of these approaches has been shown to be effective.

Long-acting interferons bound to polyethylene glycol (PEG) have several advantages. Such “pegylated” interferons, with elimination times seven-fold longer than standard interferons, achieve prolonged concentration peaks and can be administered once, rather than three times, a week. Instead of the frequent drug peaks and troughs associated with frequent administration of short-acting interferons, administration of pegylated interferons results in drug concentrations that are more stable and sustained over time. Preliminary studies suggest that once-a-week injections of pegylated interferons are at least as effective as standard interferons given three times a week and may result in sustained responses comparable to those achieved with combination interferon-ribavirin therapy.

If a patient relapses after a course of interferon monotherapy, repeating a course of interferon monotherapy is unlikely to achieve a sustained response unless the dose or preferably the duration of therapy is increased. Under these circumstances, sustained response rates as high as 40% can be realized. Although a small proportion of interferoonresponders can respond to a repeat course of interferon monotherapy, and although a 13% sustained response rate has been reported for prior interferoonresponders treated with high-dose (15 ug) consensus interferon, the likelihood of responding is not increased substantially by retreating interferoonresponders with interferon monotherapy.

Combination Interferon-Ribavirin Therapy  The most effective way to increase the efficacy of interferon therapy is to add ribavirin, an oral guanoside nucleoside. When used as monotherapy, ribavirin is ineffective and does not reduce HCV RNA levels. In contrast, the combination of interferon at standard doses with ribavirin at doses of 1000 mg (for patients weighing <75 kg) to 1200 mg (for patients weighing і75 kg) per day increases both end-treatment responses and sustained responses in previously untreated patients. Large, international, multicenter trials have shown that end-treatment responses at 6 months or 12 months exceed 50% and sustained responses as high as 33% at 6 months and 41% at 12 months have been achieved. Thus, a full year of combination therapy is twice as effective as a year of interferon monotherapy. Sustained responses were more likely in patients with low viral loads (below 2 million copies/mL), genotypes other than 1, minimal fibrosis, age <40, and females. In patients with low viral loads and non-1 genotypes, sustained response rates can be as high as 95%, and combination therapy for 24 weeks suffices, achieving the same end as continuing therapy for a full year. Therefore, for patients with low viral loads and non-1 genotypes, therapy need last only 6 months.

For those who relapse after a 6-month course of interferon monotherapy, a 6-month course of combination therapy results in a sustained response rate of 50%, and retreatment of relapsers is another approved indication for combination therapy. Unfortunately, combination therapy has been disappointing in interferoonresponders.

Side effects of combination therapy are similar to those of interferon monotherapy; however, ribavirin causes hemolysis; a reduction in hemoglobin of up to 2 to 3 gm or in hematocrit of up 5 to 10% can be anticipated. A small, unpredictable proportion of patients will experience profound, brisk hemolysis, resulting in symptomatic anemia. Therefore, close monitoring of blood counts is crucial, and combination therapy should be avoided in patients with anemia or hemoglobinopathies and in patients with coronary artery disease or cerebrovascular disease, in whom anemia can precipitate an ischemic event. Ribavirin, which is renally excreted, should not be used by patients with renal insufficiency; the drug is teratogenic, precluding its use during pregnancy and mandating the use of efficient contraception during therapy.

Ribavirin therapy has also been characterized by nasal congestion, pruritus, and precipitation of gout; the combination is more difficult to tolerate than interferon monotherapy. In one large clinical trial of combination therapy versus monotherapy among patients treated for a year, 21% of the combination group (but only 14% of the monotherapy group) had to discontinue treatment, while 26% of the combination group (but only 9% of the monotherapy group) required dose reductions.

Indications for Antiviral Therapy  Patients with chronic hepatitis C who have elevated ALT levels, detectable HCV RNA, and chronic hepatitis of at least moderate grade and stage are candidates for antiviral therapy with interferon and ribavirin, unless ribavirin is contraindicated. Preliminary retrospective analyses have shown that interferon treatment improves survival and complication-free survival. One year of combination therapy is standard, but 6 months suffice for patients with non-1 genotypes and low viral loads. For patients treated with interferon monotherapy, 12 months is the standard duration in all cases, regardless of genotype and viral load. According to the NIH Consensus Development Conference in 1997, therapy should be discontinued in patients who have not achieved a normal ALT and an undetectable HCV RNA by month three. Although the vast majority of patients treated with combination therapy who become sustained responders will have achieved an early biochemical and virologic response, a proportion of sustained responders experienced late viral clearance. In addition, even in biochemical and virologic nonresponders, histologic improvement is common. Therefore, recommendations for early cessation of therapy based on interim assessments of biochemical and virologic responsiveness require reevaluation. Although response rates are lower in patients with certain pretreatment variables, selection for treatment should not be based on symptoms, genotype, viral load, or the mode of acquisition of infection.

Patients who have relapsed after an initial course of interferon monotherapy are candidates for a 6-month course of combination interferon-ribavirin therapy; if they cannot tolerate ribavirin, they should be retreated with interferon monotherapy, but the course should be longer. It remains to be determined whether long-term (even indefinite) maintenance therapy will be necessary or effective in patients who relapse repeatedly whenever therapy is discontinued. For interferoonresponders, retreatment with interferon monotherapy or combination therapy is unlikely to achieve a sustained response. Clinical trials are in progress to determine whether long-term suppression of virus-induced liver injury with antiviral therapy will be of benefit in this population.

In patients with acute hepatitis C, a course of interferon has been shown to reduce the likelihood of chronicity by one-half. In patients with normal ALT levels, long-term monitoring studies have shown absence of histologic progression, and clinical trials of antiviral therapy have showo benefit; therefore, treatment of such patients is not recommended. Because hepatitis C can reactivate in patients with normal ALT levels, laboratory monitoring several times a year should be done, and therapy should be considered for sustained elevations in ALT levels. Patients with mild hepatitis on liver biopsy are not routine candidates for antiviral therapy, but treatment decisions should be individualized between physician and patient. Most authorities would recommend a pretreatment liver biopsy to help in the decision-making about therapy.

Patients with compensated cirrhosis can respond to therapy, although their likelihood of a sustained response is lower than ioncirrhotics. Combination therapy brings sustained response rates in cirrhotics up to the level achieved with interferon monotherapy ioncirrhotics. Retrospective analyses generally have not demonstrated an improvement in survival among interferon-treated cirrhotic patients. Similarly, several studies have suggested that treatment of cirrhotics with hepatitis C reduces the frequency of HCC; however, logistic regression analyses have shown that patient characteristics at the time of therapy (e.g., less advanced disease), not treatment itself, accounted for the reduced frequency of HCC observed in the treated cohort. Patients with decompensated cirrhosis are not candidates for antiviral therapy but should be referred for liver transplantation. After liver transplantation, recurrent hepatitis C is the rule. Most patients who undergo liver transplantation for chronic hepatitis C experience little, if any, morbidity, allograft loss, or mortality associated with recurrent hepatitis C during the early postoperative years; studies are in progress to determine how best to treat hepatitis C after liver transplantation. The cutaneous and renal vasculitis of HCV-associated essential mixed cryoglobulinemia may respond to interferon, but sustained responses are rare after discontinuation of therapy; therefore, prolonged, perhaps indefinite, therapy is recommended in this group.

Anecdotal reports suggest that antiviral therapy may be effective in porphyria cutanea tarda or lichen planus associated with hepatitis C. In patients with HIV infection, responses similar to those seen in other groups have been reported in patients with normal CD4 counts.

 

BIBLIOGRAPHY

1. Eugene Braunwald, Anthony Fauci et al: Harrison’s principles of internal medicine. McGraw-Hill. Medical Publishing Division, 15^th edition, 2000.

2. Lawrence M. Tierney, Jr. et al: Current Medical Diagnosis and treatment 2000, Lange Medical Books, McGraw-Hill, Health Professions Division, 2000.

3. Christopher R.W. Edwards et al: Davidson’s  principles and practice of  medicine, 17^th edition, Educational Low-Priced Books Scheme funded by the British Government, 1995.