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



INTRODUCTION:

At best, the conventional liver tests only determine qualitatively the presence or absence of hepatobiliary injury [1,2,3,4]. The standard liver "function" tests, such as serum bilirubin, alkaline phosphatase, aminotransferases and albumin, may all be modulated by pathologic processes outside of the liver (Table 1), and none give an accurate assessment of hepatic function. Quantitative tests of liver function are being explored clinically [5], but to date none have been widely accepted in the practice of hepatology, and most have been restricted to research studies. Regardless, the differential diagnosis 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 and/or long-term management of chronic hepatobiliary disease, the presumptive diagnosis can be made in the majority of circumstances by primary care physicians. This chapter will review the principles, practice and guidelines for referral by primary care providers dealing 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 on the evaluation of abnormal liver function tests relates to the overall prevention of end stage liver disease and the consequent need for liver transplantation. To this important end, understanding the prevalence and risk factors for various chronic liver diseases, cost effective laboratory testing for early identification in different populations, and potential effective therapies are the important variables which determine the ultimate value of such an approach. Yet, the epidemiologic evidence which could provide both the prevalence of various etiologies of chronic liver disease in the United States, and the definition of risk factors remains incomplete. Although the knowledge base is limited, a recent review on the detection of chronic liver disease, as it relates to costs and benefits, may be of interest to the reader [6]. 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 affecting the biliary tract (cholestatic disease) or an infiltrative process. Hepatocellular injury usually results in the elevation of AST and ALT with little to 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 in 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 with light-colored stools and dark urine are oftentimes the presenting complaints. Physical examination can reveal fever, jaundice, scleral icterus, and mild right upper quadrant pain with hepatomegaly. In some instances, a skin rash may be 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, B, and C as well as an anti-CMV IgM and monospot. 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 a consideration including alcohol. 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 [7]. 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 to 50 days ( 30 days) with most cases completely resolved 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 [8]. The hepatitis A vaccine should be administered to individuals traveling to endemic areas, homosexually active men, intravenous drug users and persons working with nonhuman primates if there is no evidence of prior exposure [9,10]. 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 [7]. 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 [11]. It is parenterally transmitted with high-risk groups being the 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 [12]

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 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 Antibodies to core and surface antigen remain positive for many years. Acute infection resolves by 6 months in most patients, with only 5% developing 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 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 [13] 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 being 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 [14,15,16]. 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 [17,18].

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 [19,20,21]. 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 [22]. 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 [23,24]. 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 to 3 cases per 10,000 units transfused [25]. Unlike in former years, intravenous drug use is now the most common risk factor for acute hepatitis C infection which in the recent Sentinel Counties Viral Hepatitis Study was the cause of acute hepatitis in 15% of the study cohort [7]. The hepatitis C virus is a single-stranded RNA virus. It is parenterally transmitted with the most common risk factors for infection being intravenous drug use, a prior history of transfusion of blood products, intranasal cocaine use, sexual promiscuity, and ear piercing in men [26]. In other studies, tattoos have also been associated with an increased risk for hepatitis C [27]. The mechanism of hepatocellular injury is unknown, but the immune response 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 infections (see chronic liver injury). Diagnosis of acute hepatitis C infection is far from ideal. Second generation antibody assays with a sensitivity of >90% confirm prior exposure to the virus but do not differentiate between acute and chronic infection. In addition, the presence of the antibody does not imply immunity since most individuals are positive for circulating virus when tested [28,29,30]. HCV RNA measured by the quantitative branched chain DNA assay or by a more sensitive qualitative PCR will confirm the presence of circulating virus. History and physical exam as well as historical laboratory data aid in the diagnosis. Treatment is supportive. There is some preliminary evidence that suggests interferon beta as well as interferon alfa may be effective in decreasing the incidence of chronic hepatitis following an acute infection [31,32], but treatment of acute infection remains at an investigational stage.

1.5 Hepatitis E

Hepatitis E is an enterically transmitted virus which causes an acute self-limited hepatitis [33]. 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, therefore treatment is supportive.

1.6 Epstein-Barr Virus

Epstein-Barr virus (EBV) is a member of the herpesvirus group. The virus is ubiquitous causing a subclinical infection in most individuals in early childhood. It is the causative agent of infectious mononucleosis which was initially described as an illness of young adulthood [34]. 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 [35]. Infection with EBV is clinically apparent when primary exposure is delayed until adolescence and adulthood. Transmission occurs from intimate contact 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 with jaundice in only 4-10%. The hepatitis is self-limited and has no chronic sequelae. Laboratory evidence of EBV infectiion consists of atypical lymphocytosis and the presence of heterophile antibodies [36]. Since heterophile antibodies are present in at least 90% of cases of infectious mononucleosis and there are very few false postive 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 is usually asymptomatic. The prevalence of CMV antibodies varies from population to population and ranges from 40-100% with prevalence being higher in the lower socioeconomic groups. The virus is transmitted by contaminated blood, via contaminated breast milk or other body secretions [37]. The mononucleosis syndrome caused by CMV is indistinguishable on clinical grounds from that caused by EBV [36]. The accompanying hepatitis may be the initial sign of CMV infection and is often times asymptomatic. The virus can be isolated in the urine or blood and is associated with a rise in antibody titres. Granulomatous hepatitis due to CMV infection has been described in immunocompetent individuals [38]. Atypical lymphocytosis is a prominent feature. Both forms of hepatitis resolve completely without any 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 with AST and ALT elevations usually in the range of 2-5 times the upper limits of normal. Symptoms are variable depending on the underlying etiology and range from asymptomatic to symptoms of cirrhosis and liver failure. Fatigue is common. Physical signs are absent in most whereas in others signs of cirrhosis are present. Initial evaluation involves documenting a history of chronically elevated serum liver enzymes and checking hepatitis B and C serologies. If the patient has evidence of chronic hepatitis B, the 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 Steatosis/Non-Alcoholic Steatohepatitis

Steatosis or fatty infiltration

of the liver is the most common cause of liver enzyme elevation in the general population [39]. AST and ALT are usually no greater than 1 1/2 times the upper limits of normal. Patients are asymptomatic and the diagnosis is one of exclusion when all other markers of liver disease are negative. Related disorders include alcoholism, obesity, diabetes mellitus, hypertriglyceridemia, and certain drugs (Table 4). Ultrasound or CT scan can suggest fatty infiltration or be normal. Weight loss can result in improvement in laboratory tests.

Non-alcoholic steatohepatitis

is a histologic lesion that is identical to alcoholic hepatitis but found in an individual without a history of heavy alcohol use. The most common associated disorders are obesity, diabetes mellitus, and hypertriglyceridemia. Certain drugs are also associated with this lesion (Table 4). Patients are usually asymptomatic unless they have cirrhosis at the time of presentation. Liver enzyme elevations are similar to that seen in chronic viral hepatitis. This lesion can progress to cirrhosis, albeit in a small percentage of patients [40,41]. A liver biopsy may be indicated depending on the clinical situation, and therefore, the patient should be referred to Gastroenterology/Hepatology for evaluation. Treatment consists of weight reduction or removal of the offending agent.

2.2 Hepatitis B



Chronic hepatitis B infection follows an acute infection in up to 5% of individuals. It can take the form of a chronic carrier state or active hepatitis
(Table 5). Seven to 20% of patients per year can spontaneously clear HBeAg [42]. Chronic hepatitis B infection is commonly asymptomatic, and when symptoms are present they are often nonspecific, including fatigue, malaise, and myalgias. With the presence of cirrhosis, patients may present with complications of portal hypertension (ascites, edema, variceal bleeding, encephalopathy). The prognosis of a chronic carrier is excellent [43]. This relates to the fact that the liver injury is mediated by the host immune system in chronic hepatitis B infection. On the other hand, patients with chronic HBV hepatitis are at risk for eventually developing cirrhosis and hepatocellular carcinoma. A prospective study evaluating the 5-year survival rate of patients with chronic hepatitis B based on histology showed that patients with chronic persistent hepatitis had a survival of 97%, chronic active hepatitis 86%, and cirrhosis 55% with the main cause of mortality being liver failure in all groups [44].

Uncommonly, patients with chronic HBV may be coinfected with HCV, particularly in association with IV drug use. 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 [45]. The majority of individuals who develop hepatocellular carcinoma from hepatitis B have cirrhosis. The risk for the development of hepatocellular carcinoma occurs after 20 - 30 years of infection. Consequently, screening after that time period is recommended with yearly serum alfa fetoprotein levels and ultrasonography. Thus any patient with chronic hepatitis B infection of this duration should be referred to Gastroenterology/Hepatology.

Interferon alfa is the treatment of choice for chronic hepatitis B. It was initially shown to be effective in eradicating the hepatitis B virus in up to 37% of patients treated with 5 million units subcutaneously daily [46]. 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 [47]. Determination of viral level and histologic assessment prior to the initiation of therapy are therefore recommended. 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 [48]. Lamivudine (3-thiocytadine, 3-TC), was recently approved for the treatment of chronic hepatitis B [49]. The advantages of lamivudine are that it is administered orally and has relatively fewer side-effects as compared to interferon. The disadvantage is that even with prolonged therapy (up to 1 year) rates of viral clearance are low at approximately 20%.

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 [50]. Treatment with interferon alfa is disappointing, with a high rate of relapse following withdrawal of the drug [51].

2.4 Hepatitis C

An estimated 1.2% of the U.S. population is infected with the hepatitis C virus. Studies of the natural history of hepatitis C are conflicting [52,53,54]. Most epidemiologists would agree that after 10 years of infection patients can develop chronic hepatitis with fibrosis, 20 years cirrhosis, and 30 years hepatocellular carcinoma [55]. 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 not uncommonly asymptomatic with relatively normal to low level ALT elevation. Up to one-half of patients chronically infected with hepatitis C can develop cirrhosis. With cirrhosis, there is a 4-fold increased risk of hepatocellular carcinoma [56]. For these reasons, treatment of chronic hepatitis C is warranted, and all patients should be referred to Gastroenterology/Hepatology for evaluation.

Current treatment consists of combination therapy with interferon alfa 3 million units given subcutaneously thrice weekly with oral ribavirin (Rebetol) 1000 to 1200 mg/day (Rebetron=interferon + ribavirin) for 6 months to one year. Sustained response of up to 43% is seen in patients treated for 6 months to 1 year as compared to interferon alone with a sustained response rate
of only 6-19% [65,69]. In general, patients with abnormal liver enzymes should have viral quantitation and eventually undergo a liver biopsy for histologic assessment prior to treatment.

Studies have shown that higher pre-treatment viral levels and advanced histology may be negative predictors of response, while female sex and a young age may portend a favorable response [58,59,60,61,65]. Viral genotype is also important since the 1a and 1b genotypes appear to be less responsive to therapy [62,63,65]. Combination therapy is associated with multiple side-effects, therefore patients should be carefully screened prior to treatment (Table 6). Other types of interferons have been used in the treatment of chronic hepatitis with similar results [64,65,66,67,68].

2.5 Idiopathic Autoimmune Chronic Active Hepatitis

Idiopathic autoimmune chronic active hepatitis (formerly called "lupoid hepatitis") was first described in 1950 as a syndrome characterized by cirrhosis, plasma cell infiltration of the liver, and hypergammaglobulinemia in young women [70]. The etiology is unknown except that it is a disorder of immune system targeting of the liver. The natural history of untreated autoimmune hepatitis is poor with a 6 month mortality of 40% [71]. In one study, the incidence of cirrhosis in patients with bridging fibrosis and multilobular necrosis was 82% within 5 years. Only 20% of patients experienced a spontaneous remission [71]. At least 70% of patients presenting with autoimmune hepatitis are women, with the majority being less than 30 years of age (age range 9 months to 77 years) [70]. The most common presenting symptoms are fatigue, jaundice, mild abdominal discomfort, pruritus, anorexia, polymyalgias, diarrhea, delayed menarche, and amenorrhea (in order of decreasing frequency). 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 oftentimes difficult to differentiate from autoimmune liver disease. Autoimmune markers including antinuclear antibody (50-70%), antismooth muscle antibody (60%), or both (40%) are positive in many patients. Antibodies to double-stranded DNA are found in up to 40% with low-titer positive anti-mitochondrial antibodies present in 10-30% [72]. A variety of other autoimmune markers have also been found to be present. These autoimmune markers are somewhat non-specific and can be found in low titres 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 [73]. Any patient with positive autoimmune markers and abnormal liver function tests should be referred to Gastroenterology/Hepatology.

Prednisone therapy has been shown to reduce mortality from autoimmune hepatitis and is considered first-line therapy [72]. Azathioprine alone is ineffective but can be used effectively as a steroid-sparing agent. Treatment needs to be
continued indefinitely as most cases relapse after complete withdrawal of immunosuppression. Other immunosuppressive drugs have been tested in pilot studies but should be reserved for steroid-resistant cases [74,75,76].

2.6 Wilson’s Disease (Hepatolenticular Degeneration)

Wilson’s disease is an inherited autosomal recessive disease affecting approximately 1 in 30,000 individuals [77]. 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 [78]. The disease is one of abnomal 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. Liver disease in Wilson’s disease ranges from asymptomatic to fulminant; chronic active hepatitis to cirrhosis, and 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 [79]. 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 but 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 [80].

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 the nuclei of the hepatocytes [81,82]. Patients then may develop findings of chronic active hepatitis which can progress to cirrhosis or fulminant hepatic failure [83,84,85]. Treatment with chelating agents (penicillamine, trientine, British-Anti-Lewisite, zinc salts) can result in complete reversal of hepatic, neurologic and psychiatric abnormalities [86,87]. The key to successful management of Wilson’s disease is early diagnosis and treatment. For failures of chelating therapy, liver transplantation is curative.

2.7 Hereditary Hemochromatosis

Hereditary hemochromatosis (HHC) is one of the most common inherited diseases affecting 1 in 300 adults in populations of northern European origin and has a carrier rate of 1 in 20 [88,89]. It is inherited as an autosomal recessive trait with a linkage to HLA-A3 (most common associated haplotypes HLA-A3, B7 and HLA-A3,B14) in up to 75% of individuals [90]. The mutated gene has recently been located and has been designated HLA-H [91] allowing routine testing in suspected patients. This mutated gene was found in 83% of patients tested. The primary defect in iron metabolism in patients with hereditary hemochromatosis is of increased intestinal iron absorption leading to iron overload [92,93]. Dietary factors may enhance the expression of the disease, either as a source of iron or by enhancing 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.


The mean age of onset of symptoms is 50 years [94]. The most common presenting symptoms are weakness and fatigue [95]. Other symptoms are usually a reflection of extrahepatic involvement (Table 9). Liver test abnormalities are mild, usually no greater than 2 to 4-fold elevations. Iron indices are abnormal with elevated transferrin saturation and serum ferritin in 94% of affected individuals [96].

A liver biopsy is indicated for diagnosis of elevated hepatic iron as well as to assess histologic severity of disease. Genotyping is also available at specialized centers. It is at this point that a referral to Gastroenterology/Hepatology is indicated. In the earliest stages (pre-symptomatic) iron deposition is present in the periportal regions without fibrosis or inflammation. As iron accumulation progresses, chronic active hepatitis is apparent with eventual evolution into cirrhosis. The hepatic iron index (hepatic iron concentration/age) is useful for diagnosing hepatic iron overload secondary to genetic hemochromatosis [97]. A hepatic iron index greater than 1.9 can help differentiate iron overload due to genetic hemochromatosis from other causes of elevated hepatic iron. Non-invasive tests such as CT scan and MRI to assess iron overload are currently under investigation.

The goal of therapy of hereditary hemochromatosis is to decrease circulating iron stores and mobilize the tissue stores 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 would take 2-3 years to effectively deplete tissue iron stores [94]. Iron chelation with desferoxamine should be reserved for those individuals who cannot tolerate phlebotomy. Iron reduction therapy is effective in decreasing mortality from hereditary hemochromatosis in noncirrhotic patients [95]. Patients with established cirrhosis should undergo regular screening for hepatocellular carcinoma since their risk is amongst the highest of patients with chronic liver disease [95]. First-degree relatives should also undergo screening with a transferrin iron saturation, serum ferritin, and liver enzymes. If the HLA type of the proband is known, HLA typing of first-degree relatives can also identify affected individuals. If genotyping is available, this can be useful in the diagnosis of genetic hemochromatosis.

2.8 Alpha-1-Antitrypsin Deficiency


Alpha-1-antitrypsin deficiency was first described in 1965 [98]. 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 [99]. Deficiency of the enzyme is the most common inherited disorder and indication for liver transplantation in children [100]. The gene frequency is highest in populations of northern European extraction. The 26 different alleles are expressed in a codominant fashion, with PiMM being the normal phenotype and PiZZ associated with clinical disease (Table 10). In infants, a1-antitrypsin deficiency is a cause of neonatal cholestasis accompanied by elevations 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 [101]. In spite of low a1-antitrypsin levels in patients with the PiZZ phenotype, the majority do not develop liver disease [102,103].

In adults, chronic liver disease due to a1-antitrypsin deficiency is usually seen in the elderly without evidence of pulmonary disease [104]. a1-Antitrypsin deficiency should be considered in any adult presenting with chronic hepatitis or cirrhosis unknown etiology. The diagnosis should be suspected if a1-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 a1-antitrypsin deficiency with periodic acid-Schiff positive, diastase-resistant globules in periportal hepatocytes [105,106] and also to document severity of disease. Treatment is supportive and liver transplantation is curative [107]. Data regarding the risk of hepatocellular carcinoma in this disease is complicated 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 [108,109].

3.0 DRUG-INDUCED LIVER INJURY

3.1 Alcoholic Liver Disease

Acute liver injury from alcohol manifests itself in the form of alcoholic hepatitis. On the average, consumption of 80 gms of alcohol per day (equivalent to 6 bottles of beer, 30 oz. of wine, or 9 oz. of spirits) for males and 40 gms for females can result in toxic liver injury. Alcohol has direct cytotoxic effects as well as toxic metabolites, primarily acetaldehyde [110]. 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 [111]. If symptoms are present, patients can experience nausea, vomiting, abdominal pain, jaundice, gastrointestinal bleeding or new onset ascites. Fever and leukocytosis are often present 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 elevation can be helpful since in many cases the AST:ALT ratio is greater than 2,
with serum enzyme levels rarely being 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 requiring hospitalization, steroid therapy may be indicated [112]. Prognosis depends on the degree of underlying chronic liver disease which is oftentimes difficult to assess on initial presentation. The presence of encephalopathy, spider angiomas, ascites, renal failure, and prolonged prothrombin time > 50% of control are associated with an increased mortality [113]. 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. Most patients with alcoholic liver disease present in the advanced stages with cirrhosis and complications thereof. 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 assoicated with hepatic injury as well. The lay person 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 [114,115,116,117,118]. 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 are 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, consider the possibility of drug/herbal induced liver injury. Establishing the diagnosis may require re-visiting the history with the patient and family several times. Liver biopsy is rarely diagnostic but can be useful in showing chronic hepatitis, an eosinophilic infiltrate, granulomas, vascular lesions, or cholestasis. Treatment is withdrawal of the offending agent.

4.0 Liver Biopsy

Unfortunately, current imaging devices (US, CT, MRI), are not sufficiently sensitive or specific to establish 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 [119,120]. 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 [121]. 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) [2]. 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 defining extrahepatic causes of cholestasis (Table 14) [2]. 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 [122]. 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 that 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 [123]. Ultrasonography (US) is a very sensitive method for detecting gall bladder stones. Gallstones, gallbladder wall thickening, and localized tenderness over the gallbladder (Murphy’s sign) correlate highly with acute cholecystitis.

However, US is less sensitive for detecting gallstones in the common duct (choledocholithiasis), and the same is true for CT. Therefore, direct cholangiography (endoscopic or transhepatic) is necessary when choledocholithiasis is suspected.

Whereas ERCP provides a therapeutic advantage (papillotomy and stone extraction), not all patients require therapeutic intervention. Thus, magnetic resonance cholangiopancreatography (MRCP) is emerging as an alternative to ERCP [123,124].

 

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, biliary tract and extrahepatic abdomen [125]. 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 [123]. When complete delineation of the biliary tree is indicated, for example for suspected choledocholithiasis after cholecystectomy, then direct cholangiography (ERCP and /or PTC) is the procedure of choice. The choice between PTC and ERCP must be made on an individual basis although ERCP is preferred for most patients if expertise is available. The challenge to the physician is to minimize risk, expense and time necessary in obtaining 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 available [125,126]. 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 [127]. In Western countries, cholesterol gallstones are the most frequent, however in the Orient, pigment stones predominate.

The pathogenesis of each differ, and more is known about the formation of cholesterol gallstones, than pigment stones. The location of where stones form within the biliary system also varies with geography. That is, in Western countries most stones form in the gall bladder, 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 have no symptoms [127]. 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 it is associated with nausea, vomiting, fever and leukocytosis. Less commonly, gallstones can pass into the common bile duct (choledocholithasis) which in turn can lead to biliary obstruction and cholestasis. Infection (cholangitis) can follow, and 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 is diagnosed by either US/CT or cholescintigraphy [123]. US is the most common and cost effective means for gall bladder stones. Nevertheless, the sensitivity of US for small stones is not known. Endoscopic ultrasound (EUS) appears to be a more sensitive technique for detecting small gallstones and biliary sludge [126]. 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 very useful for demonstrating a stone lodged in the cystic duct. CT imaging may be more useful for addressing complications of gallstone disease such as gallbladder gangrene, or perforation, cholangitis or acute pancreatitis.

Treatment of gallstone disease is relatively straightforward. Asymptomatic stones are left alone [128]. 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 [129,130]. The management of gallstone complications may require a multidisciplinary approach [131], 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 [132].

Oral dissolution therapy, contact dissolution therapy, and extracorporeal biliary shock wave lithotripsy are special approaches to gallstone disease for patients who are not surgical candidates, a relatively small group of patients (~ 10% of patients with symptomatic gallstones) [128].

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 is bile duct stones. Cholangitis can also develop in patients with biliary stasis secondary to benign or malignant bile duct strictures. However, this occurs usually following endoscopic or percutaneous manipulation of the stricture when biliary drainage fails. In patients in whom biliary stents have been placed, either endoscopically or radiologically, cholangitis occurs 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, mostly 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 present usually in mixed infections. Antibiotics useful for treating 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 may not always be present. The onset of hypotension and mental confusion is associated with significant morbidity and mortality. In the elderly, hypotension may be the only presenting symptom. In severe cases, septicemic shock may 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 treatment of obstruction.

The principles of management of acute cholangitis are to provide drainage of the infected bile and control of 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 [132]. 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 [128]. 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, gall bladder 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 complaints. Abdominal ultrasound will diagnose a suspected leak in the majority, however, 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.

Endoscopic therapy will be successful in the majority. On occasion, both percutaneous radiologic and/or surgical approaches may be required [133]. 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 is 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 sustaining a major bile duct injury are best managed by a multidisciplinary team including invasive radiology, gastrointestinal endoscopy, and experienced biliary surgeons [129,133,134,135,136].

There has been a striking increase in bile duct injuries following laparoscopic cholecystectomy [129]. 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 presenting in the postoperative period (1-2 weeks), three presentations are seen most commonly. 1) Pain/sepsis. The first approach in this setting is imaging with US/CT to look for fluid collections (biloma or bile leaks) [137]. Appropriate antibiotics should be initiated if sepsis is present. If fluid collections are found, referral to gastroenterology/hepatology for ERCP is indicated [135]. 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 [135]. 3) External bile fistula. Refer to gastroenterology/hepatology for ERCP and/or scheduling of a fistulagram [134]. Subsequent management depends upon anatomic findings following contrast study.

Radiologic approaches to bile duct injuries, involving transhepatic catheter manipulations, offer effective therapy for patients who are unsuitable for surgical or endoscopic techniques [134]. 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 [134].

5.2.3 Biliary Tumors (Cholangiocarcinoma)



Adenocarcinomas originate in both the intrahepatic and extrahepatic bile ducts [138,139]. 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) [140].

Cholangiocarcinomas occur more commonly in younger (often less than 50 years of age) males. This 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.



The majority (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). Obtaining a histologic diagnosis may be difficult, as these tumors are very desmoplastic, and biopsy is often inconclusive.

The serum CA 19-9 determination appears to be promising for the diagnosis of cholangiocarcinoma, particularly in patients with PSC [141,142]. 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 [143,144]. A wide range of palliative approaches (endoscopic and radiologic) are available for patients in whom the disease is not amenable to surgical removal, but survival is limited [145,146]. ERCP stenting techniques can provide effective palliation of jaundice due to biliary tract neoplasms once a decision has been made not to operate [145].

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) [147,148]. 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 [148]. 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 uncommonly (10%) seen in PSC unless some type of 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. 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 appearances of beading and irregularity of the intra- and extrahepatic biliary tree occur [140]. 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 [147,148]. 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. However, in the main, 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 [149]. 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 to aid in predicting survival and the timing of liver transplantation in PSC. At this time, no medical therapy is clearly efficacious for this condition [150].

5.2.5 AIDS Cholangiopathy

HIV infected patients may develop a characteristic cholangiopathy when their CD4 lymphocyte count is low (<200) [151,152,153,154]. 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 [153]. 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 [151,152,153]. The most common pathogen, has been cryptosporidium, however, with better detection methods, microspora (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 [155]. 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 [155]

. When papillary stenosis is present, endoscopic sphincterotomy may provide symptomatic relief of pain and jaundice in some, but not all patients. 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 conidered as well as a cause for the elevating alkaline phosphatase activity [157]. Patients with diffuse intra-and extrahepatic sclerosing cholangitis alone have fewer therapeutic options. Sphincterotomy in this setting is of no benefit. Medical therapy 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 [153].

Gallbladder disease in AIDS patients often manifests as acalculous cholecystitis, although symptomatic cholelithiasis may be seen [153,154]. 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 gall bladder wall, pericholecystic fluid, stones or ductular abnormalities. The HIDA scan is often diagnostic in that there is absence of uptake of the radiolabelled material into the gall bladder [155]. Laparoscopic cholecystectomy is curative [158].

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 [121]. Ischemic injury to the bile duct can lead to post-transplant cholangiopathy, including strictures and leaks [159].
Currently, nonsurgical management (radiologic/endoscopic) is used for these biliary tract complications seen after liver transplantation [160,161]. The exact role these nonsurgical procedures play in the long-term management of strictures remains to be determined and compared with surgical therapy. Other cholestatic conditions occur in the post transplant period as well, including recurrences of PBC and PSC, drug-induced cholestasis, and a curious entity called "spinchter of Oddi dysfunction" or papillary stenosis [162,163]. The latter is not uncommon after transplantation, and the diagnosis is based upon 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 [163]. 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) [164]. 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/hepatocullar cholestasis are given in (Table 22) [121,164,165,166]. 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)
[167]. 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 [167]. 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 distinguishing 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) [167]. In this setting a liver biopsy may be required to identify a progressive ductopenia [167]. This is another circumstance where referral to hepatology/gastroenterology would be 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 [168]. 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 [168]. 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 which is compatible with or diagnostic of PBC [168]. 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 [169]. It is uncertain whether these computerized models are helpful in the decision regarding medical therapeutic interventions [170]. Ursodeoxycholic acid appears to be effective therapy for PBC [171].

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 [172,173,174]. 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 there is no difficulty in distinguishing 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 [173]. 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 [1,2,3,4]. Of the granulomatous disorders, infectious agents are the most common (Table 27) [175], however, other noninfectious causes such as sarcoidosis, need to be considered as well. Sarcoidosis may overlap with PBC and cause considerable diagnostic confusion [168]. In sarcoidosis, liver biopsy may reveal granulomas in 50 - 70% of patients, however, 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 [157]. 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 [157,176]. 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 either 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 [2,177]. 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 [178]. 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 [179]. Jaundice is rare and an ominous sign. Treatment of amyloidosis with combinations of melphalan, prednisone and colchicine is currently being investigated [180,181]. The familial form of amyloidosis, in which peripheral neuropathy is a common presentation, responds to hepatic transplantation [182].

Tumor/Abscess: Metastatic involvement of the liver, with or without a prior history of cancer, may present with an elevated serum alkaline phosphatase level [1,2,3,4,183].

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 [184,185]. Finally, on occasion, benign tumors of the liver (adenoma, focal nodular hyperplasia) may present with an alkaline phosphatase elevation [186]. 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 [187,188]. 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 [189]. 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 [190] and amebic [191]. 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.