Initial Laboratory Evaluation

Establishing an accurate serologic and virologic diagnosis of either chronic hepatitis B or C is necessary, as well as testing for other, possibly concomitant, causes of chronic liver disease. Lab studies are also necessary for establishing a pretreatment baseline, identifying advanced liver disease, or contraindications to treatment.

Serologic Diagnosis of Chronic Hepatitis B

The diagnosis of chronic hepatitis B requires evidence of viral infection with the hepatitis B surface antigen (HBsAg), which that persists for greater than 6 mo. The patient with chronic hepatitis B virus infection may be a healthy carrier with no evidence of viral replication, normal serum aminotransferase (AT) levels, and no evidence of chronic hepatitis on liver biopsy. Only those patients with chronic hepatitis B, elevated ATs, and active viral replication require consideration for treatment. The markers of ongoing viral replication that are most important to the clinician considering the patient with chronic hepatitis B include hepatitis B e antigen (HBeAg) and HBV DNA.

Most patients encountered, with chronic hepatitis B with ongoing viral replication, will be both HBeAg- and HBV-DNA-positive. There is a small group of patients with chronic hepatitis B, who have developed a pre-core mutant strain of the virus that does not produce HBeAg, and is only diagnosed by the presence of HBV DNA (7).

Occasionally, while evaluating a patient, evidence of prior hepatitis B infection will be identified by the isolated presence of the hepatitis B core antibody in the absence of HBsAg. In some instances, low-level HBV replication can be demonstrated by highly sensitive techniques, and HBsAg is present, but below the level of detectability of current assays. Management of such cases is problematic. Fortunately, this appears to be an uncommon event.

Serologic Diagnosis of Hepatitis C

For the patient with risk factors for HCV, who not infrequently has an elevated alanine aminotransferase (ALT), the screening HCV antibody test (enzyme-linked immunosorbent assay or enzyme immunoassay [EIA]) is adequate in making the serologic diagnosis of hepatitis C. The second-generation EIA blood test, developed in 1992, is 97% sensitive, inexpensive, and generally used as the screening antibody test for making the diagnosis of HCV (8). A positive EIA does not distinguish acute, chronic, or resolved hepatitis C infection, and does not indicate viremia. False-negatives can occur in immunosuppressed patients, such as the patient with chronic renal failure, or the transplant patient. Much more frequently, the clinician is faced with a false-positive EIA, which typically occurs in an individual with no risk factors and normal serum ATs. A false-positive EIA may occur in individuals with autoimmune disease or hypergammaglobulinemia of any cause.

Not infrequently, the clinician is faced with a patient identified to be HCV-positive upon blood donation, or on an insurance physical exami-

Important Information from Initial Evaluation for Developing Therapeutic Plan in Patients with Chronic Viral Hepatitis

History of present illness Date and circumstance of HCV diagnosis Initial history and date of elevated ALT Date and place of diagnosis of HCV Risk factors for bloodborne pathogens Blood transfusions prior to 1992 Injection drug use High-risk sexual practices Contact with jaundiced persons Occupational exposure

1 Tattoos and body piercing

2 Intranasal cocaine use

Household members with hepatitis or risk factors Symptoms of hepatitis Fatigue

Right upper quadrant pain

Joint pain

Pruitus

History of jaundice Nausea and anorexia Symptoms/history of advanced liver disease Jaundice Ascites or edema

GI bleeding from varices or portal hypertensive gastrophy

Review of systems HEENT: History of retinopathy Pulmonary: History of asthma or severe COPD Cardiac: History of severe or uncontrolled coronary artery disease GI: Concomitant liver disease

GU: History of renal insufficiency; document birth control MS/Rheumatology: Uncontrolled RA or severe unspecified arthritis Neurologic: History of carpel tunnel, peripheral neuropathy, or uncontrolled seizure disorder Psychiatric: History of depression, anxiety, and other psychiatric diagnoses, prior hospitalizations, prior or ongoing treatments, history of suicide attempt(s), family history of depression or suicide attempt(s)

Skin: Psoriasis, lichen planus, porphyria cutanea tarda Hematalogic/lymphatic: History of bone marrow suppression, anemia or cytopenia

Immunologic: Autoimmune diseases, document HIV testing Endocrine: History of diabetes mellitus or thyroid disease Physical exam General inspection Scleral icterus Pallor

Needle tracks

Evidence of skin excoriations Ecchymoses or petechiae

Encephalopathy Past medical history Identify history of serious illnesses including, but not limited to, severe or uncontrolled cardiopulmonary, thyroid, autoimmune, or renal disease, diabetes, or active malignancy. Complete list of current medications, including over-the-counter medications or complementary therapies Family history Family history of liver disease, hepatitis, alco, psychiatric disease, or autoimmune disease Social history

Identify psychosocial problems at home or at work Alcoholism and drug abuse Detailed history of previous and current alcoholism and drug use with quantification Family history of alcoholism and/or drug abuse History of withdrawal, blackouts or driving while intoxicated CAGE criteria for alcoholism

Muscle wasting, tenderness, or weakness Fetor hepaticus Asterixis Peripheral stigmata of liver disease Spider angiomata Palmar erythema Gynecomastia Dupuytren's contracture Paratoid enlargement Testicular atrophy Paucity of axillary and pubic hair Abdomial examination Hepatomegaly Splenomegaly Ascites

Prominent abdominal collateral veins nation, but who has no risk factors for HCV, and usually normal serum ATs. Confirmation of an HCV infection, identified by a positive screening EIA, is obtained by testing for HCV RNA, which indicates viremia and active infection.

Prior to the availability of the HCV RNA, the supplemental test used for confirmation of an HCV infection was the HCV recombinant immu-noblot assay (RIBA), which contains the same basic HCV antigens as the EIA, but is an IBA. It can confirm or refute a positive EIA in a low-prevalence population (9). The utility of the RIBA is limited, since it has been mostly replaced by the HCV RNA, when used for confirmation. However, for the patient who is identified with HCV by a positive EIA, but who has a negative HCV RNA, the RIBA is helpful in distinguishing a resolved HCV infection from a false-positive EIA.

Qualitative and quantitative polymerase chain reaction (PCR) tests are available. For HCV RNA quantification, both PCR and bDNA tests are available. The bDNA test is less sensitive than PCR, and cannot detect levels below 200,000 copies/mL blood (10). Currently, most clinicians use the quantitative PCR, rather than the qualitative PCR, for confirming diagnosis, because the viral load gives additional information when developing the therapeutic plan. The viral load has been established as a prognostic indicator for treatment outcome (1-4). A patient with a high viral load is less likely to respond to treatment, but should not be denied treatment.

Serial HCV RNA determinations are only helpful at specific time intervals during treatment, to assess response to treatment, and to make a therapeutic decision to continue or discontinue treatment (2,3). Serial HCV RNA determinations are not helpful in monitoring an untreated patient, because they are generally static over time, and do not correlate with disease progression.

There are at least six known genotypes of the HCV (11,12). Obtaining the HCV genotype is done after PCR confirmation, and prior to developing the therapeutic plan. The importance of genotyping the HCV patient became apparent in the recent U.S. and international combination trials, in which it was found that non-1 genotype patients require only 24 wk of combination therapy. In contrast, genotype-1 patients require a full 48 wk of combination therapy (2,3). The majority of patients in the United States are infected with the genotype-1 infection, and less frequently with genotype 2 and 3, which have a much greater sustained response rate, when treated with IFN alone, or in combination with ribavirin (2,3,13). The remaining non-1-genotype patients, including genotypes 4, 5, and 6, are rarely found in the United States.

Serum ATs

Not infrequently, the original diagnosis of chronic hepatitis B or C came as a result of finding an elevated serum AT at the time of a routine physical examination, as a result of blood donation, or by an insurance physical examination.

Patients with chronic hepatitis B can have a wide range of serum AT levels, from normal to markedly elevated during exacerbations. Most patients will have mild-to-moderate elevations (7). If the patient with persistently normal serum ATs is a healthy carrier of the HBV, no sero-logic evidence of viral replication will be present. In patients with viral replication and liver biopsy evidence of chronic hepatitis B, the level of the ALT has direct implications when developing the therapeutic plan. Patients with an ALT that is less than 2x elevated are less likely to respond to treatment with IFN (14-16).

For the patient with CHC, since the National Institutes of Health (NIH) consensus statement, the ALT has become the primary serum AT that is followed when considering for treatment (17). Patients with CHC can also have a wide range of ALT elevations, although most patients have a mildly elevated ALT, generally not more than twice the upper limits of normal. Hoofnagle (18) has estimated that approx 30% of patients with CHC will have a persistently normal ALT.

There is little correlation between the ALT level and disease severity, for the hepatitis C patient, although the patient with the persistently normal ALT generally has milder histologic evidence of chronic liver disease (18,19). A normal ALT associated with HCV should be repeated, to determine whether it is persistently normal (on several occasions over a period of 1 yr). This becomes important in developing the therapeutic plan, because it has been recommended that patients with persistently normal liver enzymes should not be treated outside of a clinical trial (17,20).

Baseline Lab Studies

There are a number of lab studies that are necessary for developing the therapeutic plan, which include complete blood count (CBC) renal, and liver function tests, and a baseline thyroid-stimulating hormone. The CBC and the liver function tests may be the first indication that the patient has advanced liver disease, and may not be appropriate for IFN. In addition, the finding of baseline anemia or renal insufficiency may preclude the use of ribavirin. Given that IFN is an immunomodulatory drug, it is necessary to rule out underlying autoimmune disease. In addition, other causes of chronic liver disease should be ruled out, as well (Table 2). Routine pregnancy testing prior to treatment is mandatory for

Table 2 Baseline Laboratory Testing

Autoimmune disease screening Immunoglobulins (IgG, IgM, IgA) Antinuclear Antibody (ANA) Antimitochondrial Antibody (AMA) Antismooth muscle Antibody (ASMA) Liver function and chronic liver disease screening Prothrombin time (PT) Albumin Total bilirubin Ferritin/iron studies al antitrypsin Ceruloplasmin Routine laboratory testing WBC

Hemoglobin/hematocrit Platelet count

Thyroid-stimulating hormone (TSH)

Creatinine

Glucose patients or partners of childbearing potential, because of the teratogenicity of ribarivin.

Liver Biopsy

In the United States, liver biopsy is generally recommended prior to initiating treatment for the patient with chronic viral hepatitis, unless an absolute contraindication is present. In developing the therapeutic plan, a liver biopsy serves as baseline, and helps to determine the natural history of a patient with chronic viral hepatitis. Second, it also helps to determine the sense of urgency for treatment (Fig. 1; 21). Third, the biopsy may identify cirrhosis, which may be a contraindication for the use of IFN, especially for the chronic hepatitis B patient, and also should initiate screening for hepatocellular carcinoma. Infrequently, a liver biopsy will identify other concomitant liver diseases, such as granulomatous hepatitis, alcoholic liver disease, or non-alcoholic steatohepatitis.

Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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