THE EVALUATION OF ABNORMAL LIVER FUNCTION TESTS AND JAUNDICE
Anne Larson, M.D., Carol Murakami, M.D., Richard Willson, M.D., and Susan Stover-Dalton, M.D.



INTRODUCTION:

Conventional liver tests determine only qualitatively the presence or absence of hepatobiliary injury [Chopra, 1985], [Moseley, 1996], [Kamath, 1996], [Craxi, 1996]. Standard liver "function" tests (including serum bilirubin, alkaline phosphatase, aminotransferases and albumin) can be affected by pathologic processes outside the liver (Table 1), and none give an accurate assessment of hepatic function. Quantitative tests of liver function have been explored clinically [Shrestha, 1997], but to date none have been widely accepted in the practice of hepatology; most have been restricted to research studies. Nonetheless, the etiology of abnormal liver function tests can commonly be resolved by careful clinical evaluation. The common liver function tests (LFTs) and their clinical role are outlined in (Table 2a) & (Table 2b).

Whereas referral to a gastroenterologist/hepatologist may be required for liver biopsy, ERCP, or long-term management of chronic hepatobiliary disease, primary care physicians can usually make the presumptive diagnosis for most patients with abnormal LFTs. This chapter will review the principles, practice and guidelines for referral by primary care providers who deal with abnormal liver function tests and hepatobiliary disorders. The hepatobiliary disorders will be discussed in two sections: hepatocellular injury (acute/chronic) and cholestatic injury.

This discussion of the evaluation of abnormal liver function tests relates to the prevention of end stage liver disease and the need for liver transplantation. Understanding the prevalence and risk factors for various chronic liver diseases, laboratory testing for early identification in different populations, and potential therapies are the important variables that determine the ultimate value of such an approach. However, the epidemiologic evidence, which could provide both the prevalence of chronic liver disease in the United States, as well as information on risk factors, remains incomplete. Although the knowledge base is limited, a recent review of chronic liver disease, as it relates to costs and benefits, may be of interest to the reader [Quinn, 1997]. This article discusses the role of the primary care physician and subspecialist in the evaluation of patients with asymptomatic liver function test abnormalities.

1.0 HEPATOCELLULAR INJURY: ACUTE AND CHRONIC

Definitions:

Hepatocellular injury refers to a process that involves primarily the hepatocytes as opposed to one that affects primarily the biliary tract (termed cholestatic disease) or an infiltrative process. Hepatocellular injury usually results in the elevation of AST and ALT with little or no elevation of alkaline phosphatase. The AST:ALT ratio is often useful in determining the etiology of enzyme elevation. For example, alcoholic liver disease generally is associated with an AST:ALT ratio of equal to or greater than 2:1 whereas for patients with viral hepatitis the AST:ALT ratio is usually close to or less than one.

By contrast cholestatic liver injury results in prominent elevation of the serum alkaline phosphatase (see below).

Acute Hepatocellular Injury (see algorithm 1):

Acute hepatocellular injury is apparent in patients who present with serum aminotransferase levels that are 10X the upper limits of normal and have no known prior history of liver disease. When present, symptoms are usually non-specific with flu-like symptoms: fatigue, nausea, vomiting, abdominal pain, arthralgias and occasionally diarrhea. Jaundice, light-colored stools and dark urine are oftentimes the presenting complaints. Physical examination may reveal fever, jaundice, scleral icterus, and mild right upper quadrant pain with hepatomegaly. In some instances, a skin rash is present. Chronic hepatocellular injury can also present acutely as in autoimmune hepatitis and Wilson’s disease. Symptoms and physical findings specific to these entities are discussed below. Initial evaluation includes serologies for hepatitis A IgM, hepatitis B (core antibody IgM), and hepatitis C as well as an anti-CMV IgM and monospot tests. If these are negative then autoimmune markers (anti-nuclear antibody and anti-smooth muscle antibody) and a serum ceruloplasmin should be checked. Drug and alcohol usage should also be ascertained. Liver enzymes as well as prothrombin time should be monitored weekly until there is evidence of improvement. Treatment for the individual diseases is discussed below.

HEPATOCELLULAR INJURY: ETIOLOGY/DIAGNOSIS/TREATMENT

ACUTE HEPATITIS

1.1 Hepatitis A

The most common cause of acute hepatitis is viral disease, with hepatitis A accounting for the majority of cases in the United States [Alter, 1997]. Hepatitis A is a RNA virus that is found in humans and primates. The virus is transmitted from an infected host by the fecal-oral route. Viremia is transient whereas fecal shedding is first detected 10-20 days after infection and persists at appreciable levels for at most 10 days after the onset of jaundice. The mechanism of hepatocellular injury is unknown. Acute hepatitis A is commonly seen in children, institutionalized individuals, male homosexuals and after consumption of contaminated raw shellfish. In children, acute hepatitis A is usually an anicteric illness.

The incubation period ranges from 15 - 50 days (± 30 days) and most cases completely resolve by 6 months.

Acute infection with the hepatitis A virus (HAV) never leads to chronic liver disease and <1% of cases result in acute liver failure. The serologic diagnosis of acute hepatitis A is made by a positive IgM antibody test to hepatitis A (IgM anti-HAV) which is detectable as early as 20 days after initial exposure. The presence of the IgM antibody coincides with the rise in ALT and a decrease in the level of fecal shedding of the virus. Since all cases of acute hepatitis A eventually resolve, treatment is supportive. During the acute phase, a patient should have liver transaminases, including total bilirubin and prothrombin time checked on a weekly basis until there is obvious improvement in the level of transaminases and stabilization of the prothrombin time. The major indication for a patient to be admitted to the hospital is for dehydration or in the rare instance, liver failure. Household contacts of the infected patient should receive immune serum globulin within two weeks of exposure and be vaccinated [Koff, 1998]. The hepatitis A vaccine should be administered to individuals traveling to endemic areas, homosexual men, intravenous drug users and persons working with nonhuman primates if there is no evidence of prior exposure [Lemon, 1997], [MMWR, 1999]. However, the cost of the vaccine may be prohibitive in achieving an effective prevention program for high risk groups.

1.2 Hepatitis B

The hepatitis B virus was discovered in 1965 and was originally referred to as the Australia antigen. It is the second most common cause of acute viral hepatitis in the United States [Alter, 1997]. Unlike the hepatitis A virus, hepatitis B is a DNA virus whose structure has been well characterized. Hepatocellular injury occurs as a result of the T-cell response to the viral infection. In an individual infected with hepatitis B, the viral particles can be isolated from the blood, semen and saliva [Alter, 1977]. Hepatitis B is parenterally transmitted. High-risk groups are persons who are sexually promiscuous, intravenous drug users and patients who have received blood transfusions, among others (Table 3). After exposure, the incubation period is somewhat longer than hepatitis A, ranging from 28 days to 160 days (± 8 days) with the appearance of hepatitis B surface antigen (HBsAg) indicating active infection [Krugman, 1979].

Hepatitis B viral DNA (HBV-DNA) is also present in the serum at this time followed by the appearance of the IgM antibody to the core antigen (IgM anti-HBc) at approximately 16 weeks after the onset of clinical hepatitis. Hepatitis B antigen is also present early on as a sign of active viral replication. Antibody to core surface antigen (anti-HBs) does not appear until 24 weeks after exposure and there is a time when the only marker of infection is the anti-HBc IgM (window period). IgG antibody to core and surface antigen remains positive for many years. Acute infection resolves by 6 months in most patients and only 5% develop chronic disease. Hepatitis D coinfection should be a consideration in severe cases of acute hepatitis B (see below).

Since acute hepatitis B is a self-limited illness in most immunocompetent individuals, treatment is supportive. Fulminant hepatic failure can occur and has a high case-fatality rate, therefore patients who are diagnosed with acute hepatitis B should have weekly monitoring of liver function tests and prothrombin time until there is clear evidence of improvement. At 6 months, documentation of the clearance of HBsAg and presence of anti-HBsAg is indicated, since 5% of adult cases have persistent HbsAg positivity. Household contacts of the infected individual should receive hepatitis B immune globulin with the hepatitis B vaccine in susceptible persons [Centers for Disease Control, 1984] as post-exposure prophylaxis and prevention, respectively. Transmission precautions should be reviewed with the infected patient.

1.3 Hepatitis D (Delta agent)

The hepatitis D virus (HDV) is a small circular RNA virus that is incomplete and requires the hepatitis B virus or a similar virus for replication. Acute or chronic hepatitis D infection is only seen in individuals with acute or chronic hepatitis B infection. The epidemiology of this virus is also similar to hepatitis B since both are parenterally transmitted through contaminated blood or body secretions. The highest prevalence of HDV is among HBsAg carriers in southern Italy, other Mediterranean populations, North Africa and the Middle East [Rizzetto, 1980], [Smedile, 1983], [Alter, 1985]. In areas of lower endemicity such as the United States, northern Europe, and Australia, the prevalence of anti-delta ranges from 1-10% and is primarily seen in intravenous drug users, hemophiliacs, polytransfused patients, and institutionalized hepatitis B carriers [Reinicke, 1972], [Hershow, 1989].

Acute infection with hepatitis D can occur as a coinfection with hepatitis B or as a superinfection in a chronic hepatitis B carrier.

Coinfection with hepatitis D should always be suspected in a patient who presents with severe acute hepatitis B since it is associated with a higher incidence of fulminant hepatitis [Caredda, 1985], [Smedile, 1982], [Govindarajan, 1984]. Infection with hepatitis D can resolve or become chronic. The diagnosis of acute HDV infection is generally based on the presence of the IgM anti-HDV or IgG anti-HDV seroconversion or both [Di Bisceglie, 1989]. Hepatitis D serologies should be interpreted with caution since there are a number of situations in which the presence of these markers is unreliable in distinguishing acute from chronic infection [Farci, 1986], [Smedile, 1982]. Treatment of hepatitis D infection is supportive.

1.4 Hepatitis C

Hepatitis C, formerly known as non-A,non-B hepatitis, is the most common cause of post-transfusion hepatitis. Screening of blood donors for the antibody to the hepatitis C virus in the United States was instituted in the spring of 1990 and since then, the incidence of post-transfusion hepatitis C has decreased dramatically from 45 cases per 10,000 units 0.01% to 0.001% per unit transfused [Donahue, 1992]. Intravenous drug use is now the most common risk factor for acute hepatitis C infection. In the recent Sentinel Counties Viral Hepatitis Study, hepatitis C was the cause of acute hepatitis in 15% of the study cohort [Alter, 1997]. The hepatitis C virus is a single-stranded RNA virus. It is parenterally transmitted and the most common risk factors for infection are intravenous drug use, a prior history of transfusion of blood products, intranasal cocaine use, sexual promiscuity, and ear piercing in men [Conry-Cantilena, 1996]. In other studies, tattoos have been associated with an increased risk for hepatitis C [Ko, 1992]. The mechanism of hepatocellular injury is unknown, but the virus likely plays a major role.

Most acute infections with the hepatitis C virus are asymptomatic. Once exposed to the hepatitis C virus, it becomes detectable in the serum by polymerase chain reaction (PCR) as early as 1 week. The incubation period ranges from 14 to 160 days (± 50 days).

Unlike other forms of infectious hepatitis, 85-90% of exposures result in chronic infection (see chronic liver injury). Diagnosis of acute hepatitis C infection is far from ideal. Second generation antibody assays have a sensitivity of >95% and confirm prior exposure to the virus but do not differentiate between acute and chronic infection. In addition, the presence of the antibody does not confer immunity since most individuals are positive for circulating virus when tested [Dow, 1993], [Bresters, 1993], [Farci, 1992]. HCV RNA measured by the branched chain DNA assay or by a more sensitive PCR will confirm the presence of circulating virus. The history and physical examination as well as historical laboratory data aid in the diagnosis. Treatment is supportive. There is evidence that interferon alfa may decrease the incidence of chronic hepatitis following an acute infection [Jaeckel, 2001].

1.5 Hepatitis E

Hepatitis E is an enterically transmitted virus which causes an acute self-limited hepatitis [Krawczynski, 1993]. Outbreaks of hepatitis E infection have been reported in India, Asia, Africa, and Mexico. The infection can be particularly severe in pregnant women. Symptoms are typical of acute hepatitis with jaundice, malaise, anorexia, abdominal discomfort, and hepatomegaly. Antibody tests directed to the hepatitis E viral antigen are available in specialized laboratories for diagnosis. Liver biopsy reveals findings of acute hepatitis. The infection is self-limited and treatment is supportive.

1.6 Epstein-Barr Virus

Epstein-Barr virus (EBV) is a member of the herpesvirus group. The virus is ubiquitous and causes a subclinical infection in most individuals, usually in early childhood. It is the causative agent of infectious mononucleosis, also an illness typically found in young adulthood [Sprunt, 1921]. EBV primarily infects B lymphocytes and human nasopharyngeal cells. Antibodies to EBV can be demonstrated in 90-95% of adults in most populations around the world [Pereira, 1969]. Infection with EBV is clinically apparent when primary exposure is delayed until adolescence or adulthood. Transmission occurs when intimate contact occurs with an infected individual. Typical symptoms of EBV infection are sore throat, fever, and lymphadenopathy. Elevation of liver transaminases can be seen in 80-90% of cases and jaundice in only 4-10%. The hepatitis is self-limited and has no chronic sequelae. Laboratory evidence of EBV infection includes atypical lymphocytosis and the presence of heterophile antibodies [Schooley, 1996]. Since heterophile antibodies are present in at least 90% of cases of infectious mononucleosis and there are very few false positive tests, there is no need for Epstein-Barr virus-specific antibodies in making the diagnosis of acute EBV infection except in the heterophile antibody negative cases. Signs and symptoms of the disease usually resolve over a 2-3 week period.

1.7 Cytomegalovirus

Cytomegalovirus (CMV) is a member of the herpesvirus family and like EBV, initial infection in immunocompetent individuals is usually asymptomatic. The prevalence of CMV antibodies varies from population to population and ranges from 40-100%, with higher prevalence rates found in lower socioeconomic groups. The virus is transmitted by contaminated blood, contaminated breast milk or through other body secretions [Ho, 1995]. The mononucleosis syndrome caused by CMV is indistinguishable on clinical grounds from that caused by EBV [Schooley, 1996]. The accompanying hepatitis may be the initial sign of CMV infection and is often asymptomatic. The virus can be isolated in the urine or blood and is associated with a rise in antibody titer. Granulomatous hepatitis due to CMV has been described in immunocompetent individuals [Bonkowsky, 1975]. Atypical lymphocytosis is a prominent feature. Both forms of hepatitis resolve completely without chronic sequelae.

2.0 CHRONIC HEPATOCELLULAR INJURY (see algorithm 2):

Chronic hepatocellular injury is defined by the presence of abnormal liver enzymes for greater than 6 months. The degree of serum enzyme elevation is less than in acute hepatocellular injury; AST and ALT elevations usually range from 2-5 times the upper limit of normal. Symptoms vary according to underlying etiology. Patients may be asymptomatic or present with signs and symptoms of cirrhosis and liver failure. Fatigue is common.

Initial evaluation involves documentation of chronically elevated serum liver enzymes and checking hepatitis B and C serologies. If the patient has evidence of chronic hepatitis B, antibody to hepatitis D should also be checked, especially if the patient is in a high-risk group. Other diseases to consider are autoimmune liver disease, Wilson’s disease, hemochromatosis, alpha-1-antitrypsin deficiency, and steatosis/steatohepatitis. Details regarding evaluation and treatment of these diseases are discussed below.

CHRONIC HEPATITIS

2.1 Nonalcoholic Fatty Liver Disease

Nonalcholic fatty liver disease (NAFLD) is the term used to describe a spectrum of liver disease ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with inflammation, fibrosis and liver failure. Hepatic steatosis is more common among obese persons, diabetics or persons with glucose intolerance, and Mexican Americans. The natural history and clinical significance of NAFLD are, as of yet, poorly defined. It is believed that only a small proportion progress from simple steatohepatitis to cirrhosis and liver failure [Sanyal, 2002]. Unfortunately, due to lack of prospective, unselected cohort studies of the natural history of NAFLD it is impossible to quantitate these two proportions with any degree of accuracy. For the same reason, it is impossible to predict the clinical importance of NAFLD for an individual patient. Therefore, medical treatments other than weight loss and exercise are not currently recommended. It is also questionable how aggressively to pursue the diagnosis of NAFLD, especially whether a biopsy should be performed on all patients suspected of NAFLD [Clark, 2002].

The proposed mechanism of hepatic steatosis and steatohepatitis involves insulin resistance, hyperinsulinemia, and elevated levels of circulating free fatty acids. NASH is frequently associated with obesity, type 2 diabetes mellitus, and dyslipidemia. These findings of abdomical obesity, hypertension, glucose intolerance, hypertriglyceridemia, and low HDL cholesterol have been termed the metabolic syndrome, and are frequent findings among patients with NASH. In fact, some studies have documented that insulin resistance is almost a universal finding in patients with NAFLD and have suggested that NAFLD is the hepatic manifestation of the metabolic syndrome [Marchesini, 2001], [Marchesini, 1999]

Steatosis or fatty infiltration of the liver is the most common cause of liver enzyme elevation in the general population [Sheth, 1997]. Macro and micro-vesicles of fat accumulate within hepatocytes (Figure 8). Most subjects have elevation of AST and ALT between 1 and 4 times the upper limits of normal (usually with the ALT greater than the AST). Most patients are asymptomatic. Hepatomegaly is the most common physical finding, although overall it is relatively uncommon. Although liver biopsy is the most sensitive method for detecting and staging this conditions, the diagnosis is often presumptive and made in the setting of negative markers for other liver diseases in conjunction with imaging studies that suggest hepatic steatosis. Related disorders include alcoholism, obesity, diabetes mellitus, and hypertriglyceridemia. Certain drugs are also associated with hepatic steatosis (Table 4). With most drugs (except alcohol) the steatosis tends to be purely microvesicular and therefore can be distinguished on biopsy from the steatosis of NAFLD which is macrovesicular or mixed. Ultrasound or CT scan can suggest fatty infiltration or can be normal. Ultrasonographic findings of diffuse fatty change in the liver include a diffuse hyperechoic echotexture, increased liver echotexture compared with the kidney, vascular blurring and deep attenuation [Sanyal, 2002]. Weight loss can result in improvement in laboratory tests.

Non-alcoholic steatohepatitis (NASH)

is a subset of nonalcoholic fatty liver disease. The term NASH is used as a diagnosis in patients with a lesion that is identical to alcoholic hepatitis on liver biopsy but who lack a history of heavy alcohol use. Three diagnostic criteria have been proposed for a diagnosis of NASH: (1) Histologic findings of steatohepatitis, (2) convincing evidence of minimal or no alcohol consumption and (3) absence of serologic evidence of viral hepatitis [Sanyal, 2002]. Histologic findings of steatohepatitis include accumulation of fat vescicles within hepatocytes in the setting of focal hepatic inflammation and hepatocyte death. These findings can also occur in the setting of alcoholic liver disease and drug-induced hepatitis; these must be distinguished based on clinical history. The most common associated disorders are obesity, diabetes mellitus, and hypertriglyceridemia. Drugs associated with this fatty liver are shown in (Table 4). Liver enzyme elevations are similar to that seen in chronic viral hepatitis. This lesion can progress to cirrhosis, ableit in a small percentage of patients [Sheth, 1997], [Wanless, 1990]. A liver biopsy may be indicated depending upon the clinical situation, and therefore, the patient should be referred to Gastroenterology/Hepatology for evaluation.

Treatment of NAFLD

There are very limited data on the treatment of NAFLD. Weight loss is considered the mainstay of treatment, although this is based on limited evidence. [Wang, 2003], [Alba, 2003]. Patients who are overweight (body mass index > 25 kg/m2) and have NAFLD should be considered for a weight loss program. [American Gastroenterological Association, 2002]. Treatment of hypertriglyceridemia is also recommended, although it is unclear whether this benefits liver histology. Pharmacologic treatment trials of NAFLD are now focused on two classes of drugs: insulin sensitizers and anti-oxidants. Diabetes, obesity and insulin resistance are common among persons with NASH, and this has led to interest in treatment of insulin resistance as a treatment for the abnormal liver histology. There are limited data to show that the use of biguanides (metformin) or thiazolidinediones (e.g. rosiglitazone, pioglitazone) may improve liver histology in NASH. [Sanyal, 2002]. However, unless the patient is diabetic, it is recommended that these agents not be used as a treatment for NASH outside the setting of a clinical trial, especially since they may lead to weight gain and since there are still concerns of potential serious hepatotoxicity in a very small proportion (as happened with troglitazone which was removed from the marker because of this reason). No specific pharmacologic agent has been convincingly shown to be effective in NAFLD. There is limited evidence that Vitamin E (400 IU/day) may be beneficial. Betaine, a hepatoprotective factor, was shown to be beneficial for liver histology in NASH in a very small study when given twice daily. [Sanyal, 2002]. Ursodeoxycholic acid has been shown not to be effective in this condition. [Lindor, 2004]. Further clinical studies are needed. A recommended review of the epidemiology, diagnosis, pathogenesis, and treatment of NAFLD has recently been published. [Charlton, 2004].

2.2 Hepatitis B

Chronic hepatitis B infection follows an acute infection in up to 5% of adults. It can take the form of a chronic carrier state or active hepatitis (Table 5). Seven to twenty perecnt of patients per year spontaneously clear HBeAg [Lok, 1987]. Chronic hepatitis B infection is commonly asymptomatic. When symptoms are present they are often nonspecific and include fatigue, malaise, and myalgias. When cirrhosis is present, patients may present with complications of portal hypertension (ascites, edema, variceal bleeding, encephalopathy). The prognosis of a chronic nonreplicating carrier is excellent with low risk for cirrhosis and hepatocellular carcinoma (HCC) [de Franchis, 1993]. On the other hand, patients with chronic HBV hepatitis (chronic nonreplicating carrier) are at risk for developing cirrhosis and hepatocellular carcinoma. In endemic areas, patients may have as much as a 15-20% chance of progression to cirrhosis. Once cirrhosis has developed, the survival rate is 85% at 5 years. This decreases following decompensation, with estimated survival rates of 55-70% at one year and 14-35% at five years. Patients with a prolonged replicative phase carry the worst prognosis. Other reports have shown that survival is related to severity of liver disease at presentation, with 5-year survival rates of 97% for those with chronic nonreplicating carriers, 85% for those with chronic replicating hepatitis, and 55% for those with cirrhosis [Liaw, 1989], [Fattovich, 1995], [de Jongh, 1992], [Realdi, 1994].

Uncommonly, patients with chronic HBV are coinfected with HCV; this is more common if they use IV drugs. The risk of hepatocellular cancer in patients with chronic hepatitis B related liver disease is at least 7-fold higher than other patients with non-viral liver disease with the exception of hemochromatosis [Tsukuma, 1993]. The majority of individuals who develop hepatocellular carcinoma from hepatitis B have cirrhosis. The greatest risk factors for the development of HCC in patients with chronic hepatitis B are men > 45 years of age, patients with cirrhosis, and those with a family history of HCC. Patients in these high-risk categories should be screened with a combination of alfa fetoprotein and ultrasound every 6-12 months, although the optimal time interval is not known. Chronic HBV patients who do not fall into these high risk categories may still benefit from HCC screening, although the optimal method and time interval is not known.

Treatment of Hepatitis B
The goals of treatment for chronic hepatitis B are sustained suppression of hepatitis B replication and improvement of liver disease. Patients who are HBeAG-positive and who have compensated liver disease should be observed for 3-6 months for spontaneous conversion from HBeAg positivity to HBe antibody positivity prior to beginning treatment. Patients who are positive for HBsAg but negative for HBeAg and negative for HBV DNA should be monitored with liver chemistries every 6-12 months and should not undergo antiviral treatment. Options for initial treatment of chronic hepatitis B include interferon-α, lamivudine or adefovir. The endpoint of treatment is sustained seroconversion from HBeAg to anti-HBe. Patients who are candidates for treatment (those with persistent elevation of aminotransferases > 2 x normal and with serum HBV DNA > 10⁴-10⁵ copies/ml with or without HBeAg positivity) should undergo a liver biopsy prior to initiation of antiviral therapy [Lok, 2004], [Keeffe, 2004]. Patients who are HBeAg-positive but with normal ALT should not undergo antiviral treatment.

Interferon alfa is an effective treatment for chronic hepatitis B. It was initially shown to achieve loss of hepatitis B DNA by hybridization assay in up to 37% of patients treated with 5 million units subcutaneously daily for 16 weeks [Perrillo, 1991]. Predictors of response to interferon are a low HBV DNA level by hybridization assay (< 200 pg/ml), elevated transaminases (ALT > 100 IU/L), and a history of acute hepatitis [Brook, 1989]. Determination of viral level and histologic assessment are recommended prior to initiation of therapy. One cautionary note is that patients with cirrhosis are at risk for decompensation during therapy with interferon and therefore the benefits of therapy in this group must be weighed against the risk of liver failure; these patients are best treated with lamivudine or adefovir [Hoofnagle, 1993]. Lamivudine (3-thiocytadine, 3-TC) is also approved for the treatment of chronic hepatitis B [Dienstag, 1995]. The recommended dose for adults with normal renal function is 100 mg per day. The advantages of lamivudine are that it is administered orally and has relatively fewer side effects as compared to interferon. Initial treatment is for at least 1 year, and treatment for up to 6 years has been shown to be safe [Lok, 2003]. The disadvantage is that even with prolonged therapy (up to 1 year) rates of viral clearance are low at approximately 20% to 30% and drug-resistant mutants may appear, at an approximate rate of 20% per year of therapy. Lamivudine is a treatment option for patients with decompensated cirrhosis. Adefovir dipivoxil is an orally administered prodrug of adefovir. The dose for adults with normal renal function is 10 mg per day. Adefovir inhibits HBV reverse transcriptase and DNA polymerase, and has been shown to be effective in suppressing replication of wild-type HBV as well as lamivudine-resistant HBV mutants. Adefovir is more expensive than lamivudine and is administered for at least 1 year as initial treatment. In patients with lamivudine-resistant mutations, adefovir should be considered as first line antiviral therapy. In patients with HBeAg-negative chronic HBV (elevated aminotransferases, HBeAg-negative, HBV DNA > 10⁴ copies/ml), longer duration of therapy is usually required, so adefovir is preferred over lamivudine due to the significantly lower incidence of drug-resistant mutations.

2.3 Hepatitis D

The epidemiology and diagnosis of HDV infection have been previously summarized. All patients with chronic hepatitis B infection should be tested for hepatitis delta virus infection, especially if they are in a high-risk group. There is some evidence that coinfection with hepatitis D may hasten the progression to cirrhosis [Kanel, 1984]. Treatment with interferon alfa is disappointing, with a high rate of relapse following withdrawal of the drug [Farci, 1994].

2.4 Hepatitis C

Four million persons in the United States are estimated to have been exsposed to and three million to be infected with the hepatitis C virus. There are conflicting studies of the natural history of hepatitis C [Seeff, 1992], [Alter, 1992], [Tong, 1995]. Most epidemiologists would agree that after 10 years of infection patients may develop chronic hepatitis and fibrosis, after 20 years cirrhosis, and after 30 years hepatocellular carcinoma [Kiyosawa, 1982]. As with chronic HBV infection, most patients with chronic HCV are asymptomatic. Moreover, there is a lack of correlation between the level of serum ALT, symptoms and liver histopathology. Accordingly, cirrhotic patients are commonly asymptomatic with normal transaminases or low level ALT elevation. Up to one-half of patients chronically infected with hepatitis C can develop cirrhosis. With cirrhosis, there is a 5-7-fold increased risk of hepatocellular carcinoma [Tsukuma, 1993]. For these reasons, treatment of chronic hepatitis C is warranted, and all patients should be referred to Gastroenterology/Hepatology for evaluation.

In general, in order to determine the need for treatment in a patient who is anti-HCV positive by EIA, the following should be assessed:

Other factors that favor sustained vriologic response are low pretreatment HCV RNA level, younger age, lower body weight and absence of bridging fibrosis and cirrhosis [Lau, 1993], [Pagliaro, 1994], [Jouet, 1994], [Alberti, 1993]. Viral genotype is the most important predictor of response; genotypes 1a and 1b are less responsive to therapy [Poynard, 1998], [Yoshioka, 1992], [Zein, 1996]. Treatment is associated with multiple side effects, and patients require frequent, care monitoring during treatment (Table 6). Side effects are similar for combination therapy with peginterferon and non-pegylated interferon.

2.5 Autoimmune Hepatitis (AIH)

Autoimmune hepatitis (formerly called "lupoid hepatitis" or “idiopathic autoimmune chronic active hepatitis) was first described in 1950 as a syndrome characterized by cirrhosis, plasma cell infiltration of the liver, and hypergammaglobulinemia in young women [Czaja, 1984], [Johnson, 1993]. The etiology is unknown except that it is a complex disorder of the immune system targeting the liver. There are essentially two types of autoimmune hepatitis. Type I is the predominant form seen in the United States, with only 4% comprising type II. AIH is more often seen in women (3.6:1), with a bimodal distribution (ages 10-20 and ages 45-70) [Czaja, 2002]. All ethnic groups are susceptible. The presentation ranges from asymptomatic discovery to nonspecific symptoms (fatigue, jaundice, mild abdominal discomfort, pruritus, anorexia, polymyalgias, diarrhea, delayed menarche, and amenorrhea to fulminant liver failure [Kessler, 2004]. Physical findings depend on the stage of the disease, but most commonly hepatomegaly and jaundice are apparent. Associated autoimmune disorders are present in up to 48% of cases (Table 7).

Laboratory tests show elevated transaminases and hypergammaglobulinemia. Viral infection should be ruled out as an initial step, since clinically it is often difficult to differentiate from autoimmune liver disease. Autoimmune markers including antinuclear antibody (50-70%), antismooth muscle antibody (60%), or both (54%) are positive in many patients. Anti-actin antibodies are more specific for type 1 AIH and are becoming increasingly available in the US. Antibodies to double-stranded DNA are found in up to 40% with low-titer positive anti-mitochondrial antibodies present in 10-30% [Maddrey, 1990]. A variety of other autoimmune markers can also be present. These autoimmune markers are somewhat non-specific and can be found in low titers in patients with chronic viral hepatitis. Liver biopsy is indicated to assess disease activity and degree of fibrosis. Findings are typical of chronic hepatitis but plasma cell infiltrates can be prominent [Czaja, 1993]. Any patient with positive autoimmune markers and abnormal liver function tests should be referred to Gastroenterology/Hepatology.

The natural history of untreated autoimmune hepatitis is poor. If severe disease goes untreated, as many as 40% will die within 6 months of diagnosis. When the AST and GGT are 10-fold elevated at presentation, the 3-year mortality has been reported at 50%, with a 10-year mortality of 90%. If these enzymes are less elevated, the 10-15 year mortality is 10-50% [Soloway, 1972]. Spontaneous remission is seen in 13-20% of patients, regardless of severity [Soloway, 1972]. In one study, the incidence of cirrhosis in patients with bridging and multilobular necrosis was 82% within 5 years. Prednisone therapy has been shown to reduce mortality from AIH and is considered first-line therapy. Azathioprine alone is ineffective at achieving remission, but can be used effectively as a steroid-sparing agent to reduce or discontinue prednisone once remission is attained. Treatment may need to be continued indefinitely as most cases relapse after complete withdrawal of immunosuppression (65% within 2 years). However, once remission has been achieved, drug withdrawal can be attempted.

2.6 Wilson’s Disease (Hepatolenticular Degeneration)

Wilson’s disease is an inherited autosomal recessive disease that affects approximately 1 in 30,000 individuals [Schilsky, 1996]. The incidence may be higher in communities where consanguinity is common. The gene for Wilson’s disease has been isolated and is designated ATP7B located on chromosome 13 [Petrukhin, 1994]. The disease is one of abnormal hepatic copper metabolism leading to accumulation of the metal in the liver and central nervous system. Copper accumulation in the brain is prominent in patients with Wilson’s disease. Neurologic symptoms are characterized by motor disorders and psychiatric symptoms can be severe (Table 8). The range of onset of neuropsychiatric symptoms is variable ranging from 8 to 55 years but most commonly presents in the second and third decades. Liver disease in Wilson’s disease may be asymptomatic or present as fulminant liver failure, chronic active hepatitis, or cirrhosis. Liver disease is associated with elevated hepatic copper levels. Liver involvement is rarely seen prior to age 6 and the age at presentation is variable. The natural history of Wilson’s disease can be divided into 4 stages: stage I, the initial period of copper accumulation which is asymptomatic; stage II, acute redistribution of copper within the liver and release into the circulation with chronic active hepatitis or fulminant hepatic failure and intravascular hemolysis; stage III, the chronic accumulation of copper in the brain and other extrahepatic sites which can be fatal; and stage IV, copper chelation therapy and restoration of copper balance [Dobyns, 1979]. Any patient in whom Wilson's disease is considered a possible cause of liver disease should be referred to Gastroenterology/Hepatology.

Characteristic slit-lamp findings of Kayser-Fleischer rings are usually present in patients with neuropsychiatric symptoms. These corneal rings can be seen in other chronic hepatobiliary diseases but are easily distinguished from Wilson’s disease based on clinical and laboratory findings. Sunflower cataracts are another ophthalmologic finding less commonly seen than the Kayser-Fleischer ring. Serum ceruloplasmin levels are reduced while 24-urinary copper excretion is elevated (>100 micrograms/24 hours). Although serum ceruloplasmin levels are reduced in 95% of patient’s with Wilson’s disease, neither ceruloplasmin nor the finding of abnormal urinary copper excretion is specific for Wilson’s disease therefore additional tests are necessary to confirm the diagnosis [Sternlieb, 1978].

A liver biopsy is indicated to assess the severity of the disease and also to measure hepatic copper concentration which is elevated in the range of 250-3000 ug/g dry liver (normal 15-55 ug/g dry liver). Hepatic histopathology varies depending on the stage of the disease, with the earliest changes being moderate fatty infiltration and glycogen degeneration in nuclei of hepatocytes [Anderson, 1960], [Sternlieb, 1968]. Patients then may develop findings of chronic hepatitis, which can progress to cirrhosis or fulminant hepatic failure [Johnson, 1977], [Sternlieb, 1972], [Roche-Sicot, 1977]. Treatment with chelating agents (penicillamine, trientine, British-Anti-Lewisite) can result in complete reversal of hepatic, neurologic and psychiatric abnormalities [Deiss, 1971], [Sternlieb, 1964]. Oral zinc is a newer therapy that acts by interfering with copper absorption and by increasing copper excretion in stools. It appears to be a well-tolerated form of maintenance therapy. The key to successful management of Wilson’s disease is early diagnosis and treatment. For failures of medical therapy, liver transplantation is curative.

2.7 Hereditary Hemochromatosis

Hereditary hemochromatosis (HHC) is one of the most commonly inherited diseases. It affects 1 in 250-300 adults of of northern European origin and has a carrier rate of 1 in 10-20 [Leggett, 1990], [Edwards, 1988]. The gene for HHC is inherited as an autosomal recessive trait [Simon, 1977]. The gene for hereditary hemochromatosis is located on the short arm of chromosome 6 and is termed HFE. The major mutation is a cysteine-to-tyrosine substitution at position 282 (C282Y). This mutation is found in up to 90% of patients with genetic HHC. A second independent minor histidine to aspartic acid substitution may be seen in position 63 (H63D). [Feder, 1996], [Jouanolle, 1997] Genetic testing is now available. This allows routine testing in suspected patients. In one large study, the mutated gene was found in 83% of patients tested. The primary physiologic defect in patients with hereditary hemochromatosis is increased intestinal iron absorption leading to iron overload [Jouanolle, 1997], [Powell, 1970]. Dietary factors may enhance the expression of the disease, either as a source of iron or by enhanced absorption of dietary iron (vitamin C). Men tend to exhibit signs of the disease earlier than women since women have regular iron loss through menstruation.

If left unchecked, the mean age of onset of symptoms is 50 years [Edwards, 1980]. The most common presenting symptoms are weakness and fatigue [Niederau, 1985]. Other symptoms usually a reflect extrahepatic involvement (Table 9). Increased awareness of the disease has lead to earlier detection. The most common presenting symptoms in order of decreasing frequency are: incidental diagnosis, chronic liver disease, and joint pain (arthritis). Liver test abnormalities are mild, usually no greater than 2 to 4-fold transaminase elevations. Iron indices are abnormal with elevated transferrin saturation and elevated serum ferritin in 94% of cases [Bassett, 1984].

The advent of genetic testing (HFE mutation analysis) has made liver biopsy unnecessary in selected cases of HHC. For persons age <40 with an abnormal transferrin saturation (? 45%), who are homozygous for the C282Y mutation, a ferritin <1000 ng/mL, and normal transaminases, it is recommended that phlebotomy be performed without prior liver biopsy. For persons age ? 40, abnormal transaminases or a ferritin > 1000 ng/mL, it is recommended that a liver biopsy be performed to assess histologic severity of disease. In the earliest stages (pre-symptomatic) there is iron deposition in the periportal regions without fibrosis or inflammation. As iron accumulation progresses, chronic active hepatitis is apparent and may eventually advance to cirrhosis. The hepatic iron index (hepatic iron concentration / age) is useful to distinguish hepatic iron overload caused by genetic hemochromatosis from other causes of eleveated hepatic iron [Summers, 1990]. A hepatic iron index greater than 1.9 indicates that iron overload is due to genetic hemochromatosis. The ability of non-invasive techniques such as CT scan or MRI to quantitatively assess iron overload is currently under investigation.

The treatment goal of hereditary hemochromatosis is to decrease circulating iron and mobilize tissue stores in order to prevent organ damage. Phlebotomy is the mainstay of treatment with weekly (if tolerated) removal of 500 ml of blood (equivalent to 250 mg of iron). With this phlebotomy schedule, it takes an average of 2-3 years to effectively deplete tissue iron stores [Edwards, 1980]. Iron chelation with desferoxamine should be reserved for those individuals who cannot tolerate phlebotomy. Iron reduction therapy has been shown to decrease mortality from hereditary hemochromatosis in noncirrhotic patients [Niederau, 1985]. Patients with established cirrhosis should undergo regular screening for hepatocellular carcinoma, since cirrhosis due to HHC represents one of the highest risk groups for this cancer (estimated 200-fold increased risk) [Niederau, 1985]. First-degree relatives of persons with genetic hemochromatosis should also undergo screening with genetic testing (HFE mutation analysis).

2.8 Alpha-1-Antitrypsin Deficiency

Alpha-1-antitrypsin deficiency was first described in 1965 [Eriksson, 1965]. Alpha-1-antitrypsin is a protease inhibitor (Pi) synthesized primarily by hepatocytes that inhibits a number of proteases including leukocyte elastase. Deficiency of this enzyme can lead to liver, pulmonary, and renal disease, as well as relapsing panniculitis. The gene that encodes the glycoprotein enzyme is located on the long arm of chromosome 14 [Cox, 1982]. Deficiency of the enzyme is the most common inherited disorder and most common indication for liver transplantation in children [Schwarzenberg, 1993]. The gene frequency is highest in populations of northern European extraction. The alleles are expressed in an autosomal codominant fashion, with PiMM being the normal phenotype. Over 75 alleles have been identified. PiZZ is the phenotype most commonly associated with disease (Table 10). In infants, α1-antitrypsin deficiency is a cause of neonatal cholestasis accompanied by elevation of alanine aminotransferase. The jaundice usually resolves by 6 months, except when on liver biopsy there is a paucity of intrahepatic ducts. If jaundice persists beyond 1 year, the prognosis is poor and the child is likely to develop cirrhosis [Ibarguen, 1990]. In spite of low α1-antitrypsin levels in patients with the PiZZ phenotype, the majority do not develop liver disease [Sveger, 1976], [Sveger, 1988].

In adults, chronic liver disease due to α1-antitrypsin deficiency is usually seen in the elderly without evidence of pulmonary disease [Larsson, 1978]. α1-Antitrypsin deficiency should be considered in any adult who presents with chronic hepatitis or cirrhosis unknown etiology. The diagnosis should be suspected if α1-antitrypsin levels are less than 40% of normal. At this point referral to Gastroenterology/Hepatology should be considered. The patient should undergo phenotyping to confirm the diagnosis.

Liver biopsy is indicated to confirm the characteristic histologic findings of α1-antitrypsin deficiency with periodic acid-Schiff positive, diastase-resistant globules in periportal hepatocytes [Banda, 1988], [Sharp, 1976] and also to document severity of disease. Treatment is supportive and liver transplantation is curative [Vennarecci, 1996]. Data regarding the risk of hepatocellular carcinoma in this disease is confounded by coinfection with hepatitis B and C in many of the patients. The risk of hepatocellular carcinoma may be increased but not to the level of hereditary hemochromatosis or chronic viral hepatitis [Propst, 1995], [Elzouki, 1996].

3.0 DRUG-INDUCED LIVER INJURY

3.1 Alcoholic Liver Disease

Acute liver injury from alcohol manifests itself in the form of fatty liver or alcoholic hepatitis. Alcohol has direct cytotoxic effects as well as toxic metabolites, primarily acetaldehyde [Lieber, 1988]. It not only affects the liver but the peripheral and central nervous systems, the cardiovascular, hematopoietic and musculoskeletal systems. Most patients with acute alcoholic liver injury are asymptomatic or have hepatomegaly [Maddrey, 1988]. Symptomatic patients often complain of vague abdominal pain, anorexia, nausea, generalized weakness, or diarrhea. More severely ill patients, particularly those with alcoholic hepatitis, experience jaundice, gastrointestinal bleeding, confusion, or new onset ascites. Fever and leukocytosis are often present in this setting but infection must always be considered. The diagnosis of alcoholic liver disease is largely based on a history of heavy ethanol consumption and negative studies for other causes of acute hepatitis. The pattern of liver transaminase elevations can be helpful since in many cases the AST:ALT ratio is greater than 2, with serum enzyme levels rarely higher than 300 IU/L. The gamma glutamyl transaminase (GGT) can be markedly elevated due to enzyme induction. Liver biopsy shows steatohepatitis which in the setting of alcohol consumption is diagnostic for alcoholic hepatitis.

Treatment for most cases of alcoholic hepatitis is abstinence and supportive care. In severe cases that requre hospitalization, steroid therapy may be indicated [Alexander, 1971]. Prognosis depends on the degree of underlying chronic liver disease which is often difficult to assess on initial presentation. The presence of encephalopathy, spider angiomas, ascites, renal failure, and prolonged prothrombin time are associated with increased mortality [Carithers, 1989]. Repeated episodes of alcoholic hepatitis will eventually lead to cirrhosis.

Chronic liver disease due to alcohol can take the form of benign fatty infiltration, repeated episodes of alcoholic hepatitis with progressive fibrosis, and cirrhosis. On the average, consumption of 80 grams of alcohol per day (equivalent to 6 bottles of beer, 30 oz. of wine, or 9 oz. of spirits) for males, and 40 grams/day for females can result in toxic liver injury and cirrhosis. Most patients with alcoholic hepatitis present with cirrhosis and its complications. Treatment is supportive including abstinence.

3.2 Liver Injury Caused by Other Drugs and Alternative Medicinal Agents

Drug-induced liver injury represents a heterogeneous group of liver disorders, both acute and chronic, caused by drugs, both conventional and alternative (Table 11) (Table 12). Although alternative agents largely encompass herbal preparations, some "natural" substances including vitamins (A and niacin), cocaine, mushrooms and mold (aflatoxins) have been associated with hepatic injury as well. The layperson has the common misperception that "natural" or alternative substances are safer than conventional drugs. The mechanisms by which drugs and alternative medicinal agents (herbal preparations) cause liver injury are as varied as the compounds themselves and are beyond the scope of this summary [Maddrey, 1993], [Lee, 1995], [Larrey, 1997], [Eisenberg, 1997], [Kaplowitz, 1997]. Drug-induced liver injury is a diagnosis of exclusion in most cases, or can be a contributing factor to hepatocellular injury caused by a virus or an inherited liver disease. The pattern of enzyme elevation can be indistinguishable from either acute or chronic viral hepatitis. In other cases, the clinical and histologic presentation is identical to alcoholic liver disease (Table 4). Diagnosis is based on a careful history. It is important to remember that when the clinical picture is confusing, the possibility of drug/herbal induced liver injury should be considered. In order to establish the diagnosis may it may be necessary to revisit the history several times. Liver biopsy is rarely diagnostic but can show chronic hepatitis, an eosinophilic infiltrate, granulomas, vascular lesions, or cholestasis. Treatment is withdrawal of the offending agent.

4.0 LIVER BIOPSY

Unfortunately, currently available imaging devices (US, CT, MRI), do not have the capability to identify the type of underlying liver disease without a liver biopsy. Consequently, in the evaluation of patients with chronically abnormal liver function, a liver biopsy is recommended to establish a diagnosis. The diagnostic usefulness of a liver biopsy in this setting has been established [Van Ness, 1989], [Lebrec, 1996]. Although liver biopsy is a relatively safe invasive test, percutaneous liver biopsy is associated with significant morbidity in 0.1 % of patients and mortality in 0.01% of patients. Therefore, selection of patients for liver biopsy is important, and referral to Hepatology/Gastroenterology is necessary when the clinical setting warrants further clarification. Current consensus is that review of the liver biopsy findings in the context of the complete clinical profile (history, physical examination, biochemical testing, imaging studies) assures the ultimate diagnostic accuracy.

5.0 CHOLESTATIC LIVER INJURY:

A recent review of cholestatic liver diseases in the adult will be of interest to the reader as it is discusses the disorders reviewed in this section and also provides a very lucid outline for the evaluation of cholestatic disease in non-liver transplant patients [McGill, 1998]. In cholestasis, the liver function tests frequently include a striking increase in alkaline phosphatase activity (5 - 6x normal) as well as an increase in serum bilirubin concentration (Table 13) [Moseley, 1996]. By contrast serum aminotransferase activity is only mildly elevated and on occasion may even be normal. Although jaundice is common with cholestatic disorders it is important to note that incomplete biliary tract obstruction, either intra- or extrahepatic, may present without hyperbilirubinemia, but with a prominent increase in alkaline phosphatase activity. The serum amylase, on occasion, may also be increased and may indicate a pancreatic process as a cause for the cholestatic disorder. In cholestasis, the return to normal of a prolonged prothrombin time after administration of vitamin K is to be expected.

Clinical evaluation, which includes history, physical examination and routine liver function tests, is relatively accurate in the identification of extrahepatic causes of cholestasis (Table 14) [Moseley, 1996]. Clinical clues include abdominal pain, abdominal mass, palpable gallbladder, cholangitis and previous biliary tract surgery. However, the overlap between hepatocellular disease and cholestasis is significant; perhaps 25% of patients with suspected cholestasis have hepatocellular disease [Scharschmidt, 1983]. Thus, the clinical impression about cholestasis should be further evaluated by imaging (see below) and/or liver biopsy to establish the diagnosis and to identify the location and nature of the obstructing lesion.

The impression from the initial clinical evaluation is important and influences the subsequent evaluation. Indeed, the extent of the evaluation is determined by the clinical likelihood of finding a treatable lesion in the biliary tract. If hepatocellular disease is felt to be more likely, then imaging modalities are not likely to enhance that diagnosis and liver biopsy is more likely to provide useful information. On the other hand, if extrahepatic biliary tract disease is highly suspected, then aggressive evaluation with imaging modalities is clearly appropriate. When confronted by a patient with jaundice, the objective is to identify potentially treatable causes. The most important distinction to be made is between intrahepatic and extrahepatic cholestasis (Table 15). On occasion, after a complete evaluation, the cause for the cholestatic condition remains unclear. There are idiopathic and more esoteric causes for cholestatic liver disease, and at this juncture it would be best to refer to Hepatology/Gastroenterology for further evaluation.

5.1 Biliary Tract Imaging

Technological advances have improved diagnostic imaging of the biliary tract [Saini, 1997]. Ultrasonography (US) is a very sensitive method for detection of gall bladder stones. Gallstones, gallbladder wall thickening, and localized tenderness over the gallbladder (Murphy’s sign) have a high correlation with acute cholecystitis.

However, US is less sensitive for detection of gallstones in the common duct (choledocholithiasis), and the same is true for CT scans. Therefore, cholangiography (by ERCP, MRCP or less commonly percutaneous transhepatic cholangiography) is necessary when choledocholithiasis is suspected.

While ERCP provides a therapeutic advantage (papillotomy and stone extraction), not all patients require therapeutic intervention. Thus, magnetic resonance cholangiopancreatography (MRCP) has emerged as a non-invasive alternative to ERCP [Saini, 1997], [Meakem, 1995].

Early studies suggest that MRCP detects choledocholithiasis in over 90% of cases. In extrahepatic obstructive jaundice, both US and CT may be used in the initial evaluation. Whereas US is currently cheaper, CT eliminates the operator dependency of US, and provides a more comprehensive analysis of the liver, pancreas, biliary tract and extrahepatic abdomen [Zeman, 1995]. With current technical advances, the cost differences between the two procedures will favor CT, making it the more attractive imaging modality for the hepatobiliary system [Saini, 1997]. When complete delineation of the biliary tree is indicated, e.g. for suspected choledocholithiasis after cholecystectomy, then direct cholangiography (ERCP) is the procedure of choice. Percutaneous cholangiography (PTC) is an alternative technique to visualize the biliary system, but ERCP is preferable for most patients. If local expertise is available, endoscopic ultrasound (EUS) is an alternative technique to rule out common bile duct stones. The challenge for the physician is to minimize the risk, expense and time necessary to obtain sufficient information for definitive diagnosis and treatment of cholestasis. In the field of hepatobiliary imaging, the technology continues to change rapidly. Hence current recommendations in the evaluation of hepatobiliary disorders may require revision as newer diagnostic (for example, endoscopic ultrasonography [EUS]) and therapeutic modalities become more widely available [Zeman, 1995], [Dahan, 1996]. Nevertheless, the importance of careful clinical evaluation (history, physical examination, basic liver function tests) needs to be stressed prior to the application of any diagnostic imaging modality.


5.2 Cholestatic Liver Injury - Extrahepatic: Etiology/diagnosis/treatment

5.2.1 Gallstone Disease

Gallstones are a major cause of morbidity and mortality worldwide [Johnston, 1993]. In Western countries, cholesterol gallstones are the most frequent. In the Orient, pigment stones predominate.

The pathogenesis of cholesterol and pigment stones differs, and more is known about the formation of cholesterol gallstones. The location of stone formation within the biliary system also varies with geography. That is, in Western countries most stones form in the gallbladder, whereas in the Orient, stones commonly form in the intra- and extrahepatic biliary ducts. Because of the geographic differences in both stone composition and location, the management of gallstone disease will vary geographically as well.

At least 10% of adults have gallstones. The prevalence varies with age, sex, and ethnic group. Surveys have shown a female predominance (2:1) in the younger age groups but this is less prominent with advancing age. The risk of gallstones is associated with child bearing, estrogen replacement therapy, and oral contraceptive use but not with diabetes mellitus. The development of biliary sludge has been described with ceftriaxone as well as with octreotide therapy (Table 15). The prevalence of gallstones is high in Scandinavians, Chileans and Native Americans. It is also high in obese people and those who lose weight rapidly. Important clinical risk factors for gallstone development are listed in (Table 16).

Clinically most people with gallstones are asymptomatic [Johnston, 1993]. The most common symptom of gallstones is intermittent epigastric or right upper quadrant pain, probably caused by stone impaction in the cystic duct. This biliary pain is generally a steady pain that can last for several hours; it is not a true colic. It has a diurnal rhythm and often peaks in the late evening. Although biliary pain typically occurs after eating, intolerance to fatty foods is not specific for gallstone disease and can be due to esophageal reflux, nonulcer dyspepsia or the irritable bowel syndrome. Some patients may present with acute cholecystitis. In this setting, the pain is more severe, and is associated with nausea, vomiting, fever and leukocytosis. Less commonly, gallstones can pass into the common bile duct (choledocholithiasis) which in turn can lead to biliary obstruction and cholestasis. Infection (cholangitis) can follow; this is a serious complication of gallstone disease. Finally, gallstones may pass through the ampulla of Vater and be associated with acute pancreatitis, another serious complication of gallstone disease.

Gallstone disease can be diagnosed by either US, CT or less commonly cholescintigraphy [Saini, 1997]. US is the most common and cost-effective means of diagnosis for cholelithiasis. Nevertheless, the sensitivity of US for small stones is not known. Endoscopic ultrasound (EUS) appears to be a more sensitive technique for detection of small gallstones and biliary sludge [Dahan, 1996]. Regardless, clinically important biliary microlithiasis and sludge may be too small to be detected by imaging modalities generally available in many hospitals. Cholescintigraphy (HIDA scan) is useful for demonstrating a stone lodged in the cystic duct, although the diagnosis of cholecystitis can usually be made on the basis of clinical and ultrasound/CT findings. CT imaging may be more useful to address complications of gallstone disease such as gallbladder gangrene or perforation, and to assess complications of acute pancreatitis.

Treatment of gallstone disease is relatively straightforward. Asymptomatic stones are left alone [Goldschmid, 1993]. Acute cholecystitis demands cholecystectomy (open or laparoscopic). Laparoscopic cholecystectomy reduces the number of hospital days, pain, disability, and size of scar, as compared with open cholecystectomy [Strasberg, 1995], [Majeed, 1996]. The management of gallstone complications may require a multidisciplinary approach [Erickson, 1995], and therefore requires referral to Hepatology/Gastroenterology. Bile duct obstruction, with or without cholangitis, requires drainage (usually endoscopic, occasionally radiologic, and rarely, surgical) and antibiotic coverage for acute cholangitis, as discussed below [Lai, 1992].

Oral dissolution therapy, contact dissolution therapy, and extracorporeal biliary shock wave lithotripsy are special approaches to gallstone disease for the relatively small group of patients who are not surgical candidates (~ 10% of patients with symptomatic gallstones) [Goldschmid, 1993].

Acute cholangitis is caused by bacterial infection in the biliary tree associated with biliary stasis. Factors that predispose to stasis within the biliary tree, such as stones or strictures, favor bacterial multiplication. The most common cause of cholangitis is bile duct stones. Cholangitis can also develop in patients with biliary stasis secondary to benign or malignant bile duct strictures. However, this usually occurs following endoscopic or percutaneous manipulation of the stricture if biliary drainage was not achieved. In patients in whom biliary stents have been placed, either endoscopically or radiologically, cholangitis can occur as a late complication of stent blockage by biliary sludge. Uncommonly, cholangitis can develop secondary to parasitic infestation of the bile ducts with Ascaris, Clonorchis, or Fasciola species.

The bacteriology of acute cholangitis often yields a mixed growth of Gram negative and Gram positive bacteria, of intestinal origin. E. coli is the most common Gram negative bacteria isolated from bile followed by Klebsiella sp. and Enterobacter sp. The most common Gram positive organisms include S. fecalis and Enterococcus. Anaerobic bacteria, such as Bacteroides and Clostridium species, are usually present in mixed infections. Antibiotics useful for treatment of cholangitis include third generation cephalosporins, aminopenicillins, and penicillin/B-lactam inhibitor combinations.

Clinically, acute cholangitis presents with the typical Charcot’s triad, which includes right upper quadrant pain, fever and jaundice. However, all three features are not always present. The onset of hypotension and mental confusion is associated with significant morbidity and mortality. In the elderly, hypotension may be the only symptom on presentation. In severe cases, septic shock can lead to multiorgan failure. Biochemical testing usually reveals an elevated serum bilirubin, alkaline phosphatase and/or gamma glutamyl transpeptidase activity. Noninvasive imaging studies including US and CT scanning) usually show the presence of gallbladder stones and bilary ductal dilatation associated with obstruction of the common bile duct. ERCP is recommended for both direct examination of the bile ducts and relief of obstruction.

The management principles of acute cholangitis are to provide drainage of the infected bile and to control the infection with antibiotics. In the treatment of acute cholangitis, urgent endoscopic biliary drainage (ERCP) provides a significantly lower morbidity and mortality compared with emergency surgery [Lai, 1992]. Endoscopic sphincterotomy and stone extraction is an effective method for removal of common bile duct stones. The success rate ranges between 85 - 90%. Large stones and intrahepatic stones remain technically difficult to manage nonoperatively.

5.2.2 Biliary Injuries Associated with Cholecystectomy

Ninety to 95% of bile duct injuries occur following cholecystectomy [Goldschmid, 1993]. The remainder occur following common bile duct operations, gastrectomy or pancreatic resection. Most bile duct injuries are not recognized at the time of surgery but usually become apparent in most within a week or two following surgery. A predictive factor for the development of a bile leak is a complication at the time of the laparoscopic cholecystectomy and the need to convert to an open cholecystectomy. The complications include bile duct injuries, gallbladder injuries, bleeding and liver laceration. Most patients present early (within 5 days) in the post-operative period. Abdominal pain, fever and tenderness are the common presenting complaints. Abdominal ultrasound will diagnose a suspected leak in the majority of cases; CT will be necessary on occasion. HIDA scanning appears to be the least successful of the three imaging modalities for detection of a leak. ERCP will usually define the anatomic location of the leak and is the technique of choice to provide therapy.

Endoscopic therapy will be successful in the majority. On occasion, both percutaneous radiologic and/or surgical approaches may be required [Barkun, 1997]. A small percentage of patients will remain asymptomatic for a prolonged period of time and present in a delayed fashion with evidence of a biliary stricture. Long-term results with operative repair of bile duct injuries are quite good. Outcome is determined by the nature of the injury, the type of reconstruction performed, and the experience of the surgeon. The best treatment of bile duct injuries is their prevention. Patients who sustain a major bile duct injury are best managed by a multidisciplinary team that includes invasive radiology, gastrointestinal endoscopy, and experienced biliary surgeons [Strasberg, 1995], [Barkun, 1997], [vanSonnenberg, 1993], [Kozarek, 1994], [Bergman, 1996].

There has been a striking increase in bile duct injuries following laparoscopic cholecystectomy [Strasberg, 1995]. The major risk factors for the biliary injury are lack of surgical experience, underlying inflammation and unusual anatomy. The direct causes are errors of anatomical identification and technical issues. For patients who present in the postoperative period (1-2 weeks), three presentations are most common: 1) Pain/sepsis. The first approach in this setting is imaging with US/CT to look for fluid collections (biloma or bile leaks) [Ward, 1995]. Appropriate antibiotics should be initiated if sepsis is present. If fluid collections are found, referral to gastroenterology/hepatology for ERCP is indicated [Kozarek, 1994]. Cystic duct leaks are easily managed by endoscopic techniques. Bile duct injuries in continuity with the biliary tract can almost always be managed endoscopically; the role of reoperative surgery is still not fully defined. 2) Jaundice. Refer to gastroenterology/hepatology for ERCP and/or PTC [Kozarek, 1994]. 3) External bile fistula. Refer to gastroenterology/hepatology for ERCP and/or a fistulogram [vanSonnenberg, 1993]. Subsequent management depends upon anatomic findings following contrast study.

Radiologic approaches to bile duct injuries involve transhepatic catheter manipulation and offer effective therapy for patients who are unsuitable for surgical or endoscopic techniques [vanSonnenberg, 1993]. Traditional transhepatic catheter placement allows both stenting and balloon dilatation. Biliary strictures may be successfully treated by transhepatic balloon dilatation. Biliary leaks following laparoscopic cholecystectomy induced duct injury may also be treated radiologically by percutaneous aspiration of bilomas, stent placement and transhepatic biliary diversion if necessary [vanSonnenberg, 1993].

5.2.3 Biliary Tumors (Cholangiocarcinoma)

Adenocarcinomas originate in both the intrahepatic and extrahepatic bile ducts [Tompkins, 1990], [Vauthey, 1994]. These tumors arise from either bile duct epithelial cells or from periductal glands. Extrahepatic adenocarcinomas comprise 99% of cholangiocarcinomas and are commonly divided into proximal, middle and distal (ampullary) tumors. Occasionally, cholangiocarcinomas are diffuse and involve both the intra- and extrahepatic ducts, and can mimic primary sclerosing cholangitis (PSC) [Meenan, 1996].

Cholangiocarcinomas occurs more commonly in younger (often less than 50 years of age) males. This young age predilection is explained by an association with primary sclerosing cholangitis (PSC) and coexisting inflammatory bowel disease. PSC is the most important risk factor for cholangiocarcinoma in Western countries. Other documented associations include biliary parasite infections (Clonorchis), intrahepatic stones, Caroli’s disease and choledochal cysts. The common factor appears to be chronic stasis and/or inflammation in the biliary tree.

Over 90% of patients present with jaundice. Most have pruritus and many have weight loss, anorexia or vague abdominal discomfort. There are usually few physical findings other than jaundice. Biochemical testing shows a cholestatic pattern with hyperbilirubinemia and elevated alkaline phosphatase activity. Imaging studies (see algorithm 3) will often show biliary ductal dilation and direct cholangiography (ERCP, PTC) will reveal a focal biliary stricture. The cholangiographic appearance is about 90% specific for malignancy, but other conditions that can mimic this finding are given in (Table 17). A histologic diagnosis may be difficult to obtain, as these tumors are very desmoplastic, and biopsy is often inconclusive.

The serum tumor marker CA 19-9 appears to hold promise for the diagnosis of cholangiocarcinoma, particularly in patients with PSC [Ramage, 1995], [Tan, 1995]. The prognosis of this tumor is relatively poor. The overall median survival has been from 3 -11 months. Aggressive surgical intervention is warranted for highly selected patients where tumor free margins can be obtained [Bismuth, 1992], [Nagorney, 1993]. A wide range of palliative approaches (endoscopic and radiologic) is available for patients in whom the disease is not amenable to surgical removal, but survival is limited [Kozarek, 1996], [Lee, 1993]. ERCP stenting techniques can provide effective palliation of jaundice due to biliary tract neoplasms once a decision has been made not to operate [Kozarek, 1996].

5.2.4 Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) has a male predominance (2:1), with a median onset at age 30 (age range 1 - 90 years) [Ponsioen, 1998], [Lee, 1995]. The prevalence of PSC in the United States has been estimated at 2 - 7 cases per 100,000 of the population. It is apparent that PSC is more common than previously suspected and the prevalence may actually be similar to that reported for primary biliary cirrhosis (PBC) (estimated at 10 - 15 cases per 100,000 of the population). It has been established in PSC that there is an increased prevalence of HLA antigens B8 and DR3 in PSC patients, suggesting a genetic linkage. Moreover, recent studies have suggested that the presence of the HLA DR 4 haplotype is associated with an adverse prognosis, more rapid progression to death and/or liver transplantation [Lee, 1995]. The most common clinical presentation is an asymptomatic patient with cholestatic liver function tests found on routine biochemical screening. Some patients may present with pruritus, fatigue, and right upper quadrant discomfort. Jaundice is seen late in the disease. Superimposed bacterial cholangitis is uncommon (~10% risk) in PSC unless a bile duct procedure has been performed, such as ERCP or surgery of the biliary tree. Associated diseases seen with PSC are shown in (Table 18) . Ulcerative colitis will be seen in approximately three quarters of the patients. The colitis paradoxically often follows a relatively benign course. However, some studies suggest that colonic cancer may be more common in patients with PSC and ulcerative colitis; these patients warrent more aggressive screening by colonoscopy. Other autoimmune disorders are seen much less commonly than in PBC.

The diagnosis of PSC is established by the cholestatic biochemical tests and the characteristic findings noted on ERCP where the cholangiographic appearance of beading and irregularity of the intra- and extrahepatic biliary tree is present [Meenan, 1996]. Thus confirmation of the diagnosis requires referral to Hepatology/Gastroenterology. Floxuridine (5 FUDR) therapy on occasion can be associated with a clinical syndrome similar to primary sclerosing cholangitis (Table 15).

The clinical course of PSC is characteristically variable and unpredictable [Ponsioen, 1998], [Lee, 1995]. Variables leading to worsening of biliary strictures and the unpredictable development of cholangiocarcinoma both contribute to the difficulty in predicting the prognosis of an individual patient with PSC. Generally, however, PSC is a progressive disease. Older age, elevated serum bilirubin level, and more severe histologic stage at the time of diagnosis are predictors of a poor prognosis [Broome, 1996]. The median survival from the time of diagnosis is approximately 10 years. In asymptomatic patients, approximately three quarters will become symptomatic with progression of liver disease at a mean of 6 years. Thus the majority of patients with PSC will eventually develop significant liver disease. The complications of PSC are shown in (Table 19).

Computerized models are currently being developed that predict survival and the timing of liver transplantation in PSC. At this time, no medical therapy is clearly efficacious for this condition [Lindor, 1997]. Trials with high dose ursodeoxycholic acid are underway.

5.2.5 AIDS Cholangiopathy

HIV infected patients may develop a characteristic cholangiopathy when their CD4 lymphocyte count is low (<200) [Cello, 1992], [Bonacini, 1992], [Wilcox, 1996], [Tanowitz, 1996]. The clinical presentation consists of fever, right upper quadrant pain and prominent elevation of the serum alkaline phosphatase. Diarrhea is a commonly associated feature because the etiologic pathogens (Table 20) usually involve the small intestine as well. Bacterial cholangitis is an infrequent complication [Wilcox, 1996]. Serum alkaline phosphatase levels are often in the 700-800 IU/L range. Mild increases in the serum aminotransferases are seen, however, jaundice is uncommon, except very late in the natural history of the disease.

Infection of the biliary epithelium is the cause of the ductal disease in most cases. However, both lymphoma and Kaposi’s sarcoma have also been implicated in some cases [Cello, 1992], [Bonacini, 1992], [Wilcox, 1996]. The most common pathogen identified has been Cryptosporidium. However, with better detection methods, Microsporidia (E. bienusi, E. intestinalis) appear to be a common cause and probably account for a majority of the unidentified pathogens in earlier studies.

Transabdominal US is probably the most cost-effective initial study. CT is best reserved for the jaundiced patient to look for intrahepatic mass lesions, adenopathy and biliary dilatation [Yee, 1995]. Patients suspected of having AIDS cholangiopathy, who have abdominal pain or jaundice should be referred to gastroenterology/hepatology for ERCP. The most common cholangiographic finding at ERCP is that of papillary stenosis in association with intrahepatic sclerosing cholangitis [Yee, 1995]

When papillary stenosis is present, endoscopic sphincterotomy may provide symptomatic relief of pain and jaundice in some, but not all patients [Cello, 1995]. Despite pain relief, the serum alkaline phosphatase level often continues to rise, perhaps reflecting the progression of the intrahepatic disease. However, drugs and other associated infections need to be considered as a cause for the elevation of alkaline phosphatase activity [Chalasani, 1996]. Patients with diffuse intra-and extrahepatic sclerosing cholangitis alone have fewer therapeutic options. Sphincterotomy in this setting is of no benefit. Medical therapies for cryptosporidiosis, microsporidiosis (exception may be E. intestinalis treatment with albendazole), and cytomegalovirus infection have not proven efficacious. AIDS cholangiography is rarely fatal but usually occurs late in the course of AIDS, and the prognosis is generally poor; median survival is about 6 - 10 months [Wilcox, 1996].

Gallbladder disease in AIDS patients often manifests as acalculous cholecystitis, although symptomatic cholelithiasis may occur [Wilcox, 1996], [Tanowitz, 1996]. As in AIDS cholangiopathy, opportunistic infections are the usual cause (Table 20). The clinical presentation includes right upper quadrant pain and fever. US many demonstrate a thickened gallbladder wall, pericholecystic fluid, stones or ductular abnormalities. The HIDA scan is often diagnostic in that there is absence of uptake of the radiolabeled material into the gallbladder [Yee, 1995]. Laparoscopic cholecystectomy is curative [French, 1995].

5.2.6 Cholestasis in the Post Liver Transplant Setting

There are several potential causes for cholestasis in the patient who has undergone liver transplantation [McGill, 1998]. Ischemic injury to the bile duct can lead to post-transplant cholangiopathy, including strictures and leaks [Greif, 1994]. Currently, nonsurgical management (radiologic/endoscopic) is used for these biliary tract complications seen after liver transplantation [Donovan, 1993], [LaBerge, 1993]. The exact role these nonsurgical procedures as compared to surgical procedures in the long-term management of strictures remains to be determined. Other cholestatic conditions occur in the post transplant period as well, including recurrent PBC and PSC, drug-induced cholestasis, and a curious entity called "sphinchter of Oddi dysfunction" or papillary stenosis [Balan, 1993], [Narumi, 1995]. Sphincter of Oddi dysfunction is not uncommon after transplantation, and the diagnosis is based on cholestatic liver enzymes, extrahepatic bile duct dilation and slow drainage of injected contrast at ERCP (an observation similar to that in AIDS cholangiopathy). Sphincter of Oddi manometry may or may not assist in the diagnosis. Treatment, as in papillary stenosis in AIDS, is sphincterotomy [Narumi, 1995]. The multiplicity of causes for cholestasis in the post transplant period usually indicates that referral to Hepatology/Gastroenterology be necessary.

5.3 Cholestatic Liver injury - Intrahepatic: ETIOLOGY/DIAGNOSIS/TREATMENT

5.3.1 Drug-Induced Cholestasis

Intrahepatic drug-induced cholestasis can be classified as hepatocellular or ductular (Table 21) [Erlinger, 1997]. Both of these categories have two further subdivisions. Under hepatocellular there is pure cholestasis and cholestatic hepatitis, whereas under ductular there is acute and chronic with ductopenia.

The drugs more commonly associated with intrahepatic/hepatocellular cholestasis are given in (Table 22) [McGill, 1998], [Erlinger, 1997], [Lee, 1995], [Lewis, 1995]. In this category, patients may present with jaundice and pruritus - the hallmark features of cholestasis. However, one or both may be lacking, and biochemical features may be the only manifestation of cholestasis. Typically, the biochemical abnormalities include mild hyperbilirubinemia (not detectable clinically, that is less than 3 mg %), striking elevations of serum alkaline phosphatase and/or gamma-glutamyl transpeptidase activities, and only minor increases in the serum aminotransferase activities.

The drugs more commonly associated with the ductular cholestasis (Drug-induced cholangiopathy) are listed in (Table 23) [Desmet, 1997]. In the acute circumstance, the clinical and biochemical manifestations may be similar to that described in hepatocellular cholestasis. Liver biopsy is necessary to distinguish the two categories [Desmet, 1997]. Thus referral to hepatology/gastroenterology would be necessary at this juncture. In some cases, fever and abdominal pain may be present, suggesting extrahepatic obstruction. Under these circumstances, an imaging modality (US/CT) may be required to aid in the differentiation of one from the other. The outcome is good, and the cholestasis resolves spontaneously. However, on occasion, prolonged cholestasis may occur (4 - 6 months).

In some cases, the cholestasis may be even more prolonged and is considered chronic (Table 24) [Desmet, 1997]. In this setting a liver biopsy may be required to identify a progressive ductopenia [Desmet, 1997]. This is another circumstance where referral to hepatology/gastroenterology is required. Immune mediated mechanisms have been proposed as the pathogenetic process leading to ductular (intralobular) injury and destruction. Drugs associated with chronic cholestasis/ductopenia are given in (Table 28). As liver biopsy is incorporated more frequently in the evaluation of this setting, more drugs are being associated with this condition. The prognosis is good, the syndrome usually resolves after six months to several years. Rarely, the syndrome is irreversible and over time biliary cirrhosis develops.

5.3.2 Primary Biliary Cirrhosis

The etiology of primary biliary cirrhosis (PBC) remains unknown, although immune mediated mechanisms are felt to be important in the pathogenesis of this syndrome [Kaplan, 1996]. It occurs predominately in females (9:1), and the median age of onset is 50 years of age. However, there is a wide age range in presentation (20 - 70 years). The prevalence of the disease varies considerably between geographic regions. Although PBC occurs in families (usually mother - daughter pairs), no genetic studies have been carried out. The most common clinical presentation is an asymptomatic patient in whom routine biochemical screening tests reveal a strikingly elevated serum alkaline phosphatase level [Kaplan, 1996]. However, patients may present with fatigue, pruritus and right upper quadrant discomfort. Less than 20% of patients will have jaundice at the time of diagnosis and less than 5% will present with evidence of portal hypertension, such as variceal bleeding or ascites. Pregnancy may either precipitate pruritus in a susceptible patient, or exacerbate the pruritus in patients known to have PBC. The diagnosis is established by biochemical results indicating cholestatic liver disease (Table 14), the presence of the antimitochondrial antibody (AMA), and a liver biopsy that is compatible with or diagnostic of PBC [Kaplan, 1996]. Thus, referral to Hepatology/Gastroenterology is necessary to establish the diagnosis. Primary biliary cirrhosis is associated with several autoimmune disorders, including sicca syndrome with or without arthritis, and autoimmune thyroiditis (Table 25).

The clinical spectrum of PBC ranges from asymptomatic, anicteric cholestasis with or with extrahepatic manifestations to severe icteric cholestasis with decompensated liver disease. The complications of PBC are shown in (Table 26). Currently, no specific features reliably predict progression from asymptomatic to symptomatic disease. However, increasing levels of hyperbilirubinemia indicates a poor prognosis. In the majority of patients, the course is progressive, however, at an unpredictable rate. Regardless of the type of presentation, the median survival is about 10 years. Because of the progressive nature of the biochemical and clinical features, various computerized models have been established to assist in predicting survival and to aid in determining the time of liver transplantation [Wiesner, 1992]. It is uncertain whether these computerized models are helpful in the decision regarding medical therapeutic interventions [Kilmurry, 1996]. Ursodeoxycholic acid appears to be effective therapy for PBC [Heathcote, 1996].

5.3.3 Autoimmune Cholangitis and Overlap Syndromes

The cholestatic forms of autoimmune liver disease include PBC and PSC. However, on occasion, patients with classic autoimmune hepatitis (Type I) may have evidence for significant cholestasis, and thus confusion arises around these so-called overlap syndromes. Some investigators have coined the term "autoimmune cholangiopathy" for these overlap syndromes [Ben-Ari, 1993], [Colombato, 1994], [McNair, 1998]. Because the treatment for cholestatic liver disease differs quite markedly from the treatment for autoimmune hepatitis, it is important to be confident with a diagnosis in order to make the appropriate therapeutic decision. In most patients it is not difficult to distinguish one type of autoimmune liver disease from another. However, the clinical presentation of autoimmune liver disease may be diverse, and, indeed, may change over time in the same patient [Colombato, 1994]. Overlap syndromes and even crossover autoimmune liver disease syndromes may occur, but they are relatively rare and should be considered and treated on an individual basis. These complex overlap syndromes usually require referral to Hepatology/Gastroenterology.

5.3.4 Miscellaneous Conditions

Granulomatous Hepatitis: Granulomatous disease may on occasion involve the liver, and present with liver function abnormalities. The most common biochemical manifestation is an elevated serum alkaline phosphatase [Chopra, 1985], [Moseley, 1996], [Kamath, 1996], [Craxi, 1996]. Of the granulomatous disorders, infectious agents are the most common (Table 27) [Newman, 1997]. However, other noninfectious causes such as sarcoidosis need to be considered as well. Sarcoidosis may overlap with PBC and cause considerable diagnostic confusion [Kaplan, 1996]. In sarcoidosis, liver biopsy may reveal granulomas in 50 - 70% of patients. Significant hepatic dysfunction is uncommon. Approximately one third of patients have hepatomegaly or a cholestatic enzyme pattern with only minimal elevation of the serum aminotransferase activities. Jaundice is uncommon and clinical evidence for portal hypertension is rare. Therapy with corticosteroids is controversial.

In patients with AIDS, mycobacterium avium complex infection can be associated with a cholestatic liver function pattern, with prominent elevation of the serum alkaline phosphatase activity [Chalasani, 1996]. On liver biopsy, poorly formed noncaseating granulomata, teeming with organisms by special stains, are seen. These lesions may also be associated with the AIDS-associated cholangiopathy syndrome. Treatment, with multiple drugs, is attempted but therapeutic efficacy is limited. Another lesion of the hepatobiliary system seen in AIDS patients is bacillary angiomatosis/peliosis hepatis [Chalasani, 1996], [Koehler, 1993]. This infection commonly presents with an elevated serum alkaline phosphatase level. Imaging of the liver with US/CT may reveal low-density lesions, of varying sizes, which represent the areas of peliosis hepatis. Antibiotic treatment with erythromycin, doxycycline, or tetracycline appears to be efficacious.

In addition to systemic granulomatous disorders, other systemic disorders, such as mastocytosis or the toxic shock syndrome, may present with a cholestatic picture [Moseley, 1996], [Mican, 1995]. Finally, atypical variants of viral hepatitis, particularly hepatitis A, may on occasion present with prominent and prolonged cholestasis (Table 15).

Amyloidosis: Amyloid infiltrates the liver, as it does other organs, and may commonly (1/3 of patients) present with hepatomegaly [Gertz, 1997]. However, liver function tests are usually normal. Rarely, the serum alkaline phosphatase activity may be elevated, and hepatic amyloidosis may present as a cholestatic syndrome [Peters, 1994]. Jaundice is rare and an ominous sign. Treatment of amyloidosis with combinations of melphalan, prednisone and colchicine is currently being investigated [Gertz, 1986], [Kyle, 1997]. The familial form of amyloidosis, in which peripheral neuropathy is a common presentation, responds to hepatic transplantation [Ikeda, 1997].

Tumor/Abscess: Metastatic involvement of the liver, with or without a prior history of cancer, may present with an elevated serum alkaline phosphatase level [Chopra, 1985], [Moseley, 1996], [Kamath, 1996], [Craxi, 1996], [Sheiner, 1994].

This is particularly so for metastatic tumor of the breast, lung and colon. In addition, primary hepatocellular carcinoma, in the setting of cirrhosis or chronic viral hepatitis may also present with a prominent elevation of the alkaline phosphatase [SanJose, 1965], [Schwartz, 1994]. Finally, on occasion, benign tumors of the liver (adenoma, focal nodular hyperplasia) may present with an alkaline phosphatase elevation [Reddy, 1995]. With extensive infiltration of the liver or obstruction of the biliary tract, jaundice is seen. Rarely, with lymphoma, a striking intrahepatic cholestatic syndrome may be seen which represents a paraneoplastic syndrome [Birrer, 1987], [Watterson, 1989]. In this syndrome, there is no direct neoplastic infiltration of the liver or biliary tree, and the mechanism is unclear. Treatment of the underlying lymphoma leads to resolution of the cholestatic jaundice. A similar paraneoplastic hepatopathy has been reported with nonmetastatic renal cell carcinoma [Strickland, 1977]. This hepatopathy (Stauffer syndrome) consists of hepatosplenomegaly, elevated serum alkaline phosphatase, and prolonged prothrombin time. Extirpation of the renal tumor leads to resolution of the hepatopathy.

An elevated serum alkaline phosphatase is commonly seen in patients presenting with liver abscesses, both pyogenic [Seeto, 1996] and amebic [Ravdin, 1995]. In the former, it may likely indicate biliary tract disease as the cause for the abscess.

SUMMARY

The role of the primary care physician in acute hepatocellular disease is one of diagnosis and supportive care while the attention of a specialist may be needed earlier in the diagnosis and management of biliary obstruction and other cholestatic liver diseases. Both chronic hepatocellular and cholestatic liver diseases generally require the long-term care of a specialist in conjunction with a primary care physician. As outlined in this chapter, the primary care physician plays a key role in the initial evaluation of new onset jaundice and abnormal liver tests.