Hepatitis B

I. What every physician needs to know.

Hepatitis B (HBV) infection is a complex disease process, causing both acute and chronic illness with varying degrees of severity among infected patients. Moreover, the clinical characteristics of HBV infection can change over time within the same individual over a period of years.

The virus itself is part of the Hepadnaviridae family, a DNA virus fully characterized in the latter half of the 20th century. In developing countries, HBV is mainly contracted through childbirth and percutaneously, whereas in developed countries transmission mainly occurs via sexual and percutaneous exposure. The most common source of infection in the US is heterosexual sex.

Through complicated mechanisms, HBV causes infection by infecting hepatocytes and hijacking their cellular machinery to propagate from cell to cell. However, it is now believed that damage to the liver is caused not by the virus per se, but rather by the immune system’s vigorous response to the virus. Both our innate and adaptive immune systems attack infected hepatocytes in an attempt to eliminate the virus. This leads to hepatocyte death, signs and symptoms of liver injury and inflammation, and in some cases, acute liver failure or eventual liver failure from cirrhosis.

Thus, the presentation of HBV depends in part on the body’s response to the virus, and can range from asymptomatic infection with normal biomarkers to symptomatic infection with evidence of inflammation of varying degrees including acute liver failure, to cirrhosis and end stage liver disease from decades of chronic infection.

II. Diagnostic Confirmation: Are you sure your patient has hepatitis B?

The presence of hepatitis B surface antigen (HBsAg) in the blood indicates current infection. In rare cases of acute infection during the so-called window period, the HBsAg will already be negative by the time testing is performed and the diagnosis depends on the detection of a positive hepatitis B core IgM antibody in the blood. This is a time after acute infection when HBsAg has become undetectable yet anti-HBs has not yet reached detectable levels. Other than this one exception, a patient does NOT have hepatitis B if the HBsAg is negative.

A. History Part I: Pattern Recognition:

Acute HBV infection may be asymptomatic or may present as a serum sickness-like illness. Common symptoms include fever, malaise, fatigue, anorexia, vomiting, abdominal pain, skin rash and arthralgias. Symptoms of liver inflammation can also occur, including right upper quadrant pain and hepatomegaly. Only 30% of patients experience jaundice in acute HBV infection. Finally, patients may also present with confusion in addition to the above, which may indicate acute liver failure, a condition requiring hospitalization and evaluation at a transplant center.

Chronic infection of HBV is most commonly asymptomatic. However, fatigue, anorexia, and failure to thrive may occur. Patient with chronic HBV that has progressed to cirrhosis may have the typical signs and symptoms of end stage liver disease including jaundice, spider angiomata, caput medusa, splenomegaly, ascites, edema, muscle wasting, gynecomastia and encephalopathy.

B. History Part 2: Prevalence:

An estimated 240 million persons have chronic hepatitis B worldwide.
U.S. incidence 1.5 per 100,000 population with an estimated 39,000 new cases of acute infection per year. There has been a drastic decrease since population-wide vaccination programs started in 1991.
Lower prevalence areas include U.S., Canada, Western Europe (less than 1%).
Higher prevalence areas include southeast Asia, China, sub-Saharan Africa (8-10%). High-risk groups: persons aged 25-44 years, male-female ratio 1.8:1, non-Hispanic blacks, Asians, Pacific Islanders, prison inmates, dialysis patients, patients with concurrent HIV/HCV infection.
High-risk behavior: injection drug use, high risk sexual behavior (unprotected sex, multiple sex partners, men who have sex with men), or workers who are exposed to blood and other bodily fluid.
Deaths from complications of chronic hepatitis B, including cirrhosis and hepatocellular carcinoma, are greater than 300,000 persons per year globally.

C. History Part 3: Competing diagnoses: other causes of hepatitis:

Acute hepatitis (ALT or AST is typically > 250 U/L and often > 1000 U/L)

Viral hepatitis: acute hepatitis A (HAV), acute hepatitis C (HCV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Herpes simplex virus (HSV)
Drugs/Toxins: Alcohol, acetaminophen (high doses) is the most common drug and a history of ingestion often present, amatoxins (mushrooms), cocaine
Autoimmune: Autoimmune hepatitis
Hereditary: Acute Wilson’s disease
Vascular: Budd-Chiari syndrome, congestive heart failure, hypotension/shock liver

Chronic hepatitis (ALT typically normal to 500 U/L)

Viral hepatitis: chronic hepatitis C
Drugs/toxins: (many, including OTC medications, herbal remedies, weight loss supplements, body building supplements)
Autoimmune: autoimmune hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC)
Hereditary: hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency

D. Physical Examination Findings.

Acute infection of HBV may be asymptomatic or may present with fever, jaundice, scleral icterus, right upper quadrant pain, hepatomegaly. Rash and arthritis are also sometimes present. Note that jaundice only occurs in 30% of acutely infected patients.

Physical exam findings in chronic HBV infection depend on the extent of liver injury. Patients with compensated or early stage disease may have a normal physical exam. Patients with cirrhosis from HBV present with classic findings of end stage liver disease (see cirrhosis chapter).

Polyarteritis nodosa occurs in 10-20% of chronically infected HBV patients.

E. What diagnostic tests should be performed?

Hepatic function panel (AST, ALT, total bilirubin, alkaline phosphatase, albumin).
PT, INR.
When acute infection is suspected, check HBSAg, anti-HBs, anti-HBc IgM and anti-HBc total.
When chronic infection is suspected, check HBsAg, anti-HBc total, HBV DNA. If initiation of treatment is being considered, also check HBeAg and anti-HBe. HBeAg and anti-HBe should not be checked as part of the initial diagnostic work-up of suspected hepatitis B.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Serum aminotransferases: AST and ALT

Typically greater than 1,000-2,000 U/L in acute HBV infection.
Variable degrees of elevation in chronic HBV infection from normal to 500 U/L.
ALT often greater than AST except when any form of liver disease has progressed to cirrhosis in which case the AST may slightly exceed the ALT level.

Bilirubin

Persistent elevation in chronic HBV infection may suggest advanced fibrosis.

Prothrombin time with international normalized ratio (INR)

Typically elevated in acute HBV infection
Monitored at the time of acute infection as a prognostic indicator for recovery or the rare progression to acute liver failure.
Persistent elevation in chronic HBV infection suggests cirrhosis.

Viral serologies

HBsAg: indicates the presence of HBV infection, does not distinguish acute from chronic infection; generally the most sensitive test for HBV infection (i.e., HBsAg can be positive when HBV DNA is negative).
Anti-HBs: indicates immunity to HBV from either prior infection or vaccination (can be negative during the window period of acute infection); titer can drop to undetectable levels decades after infection.
Anti-HBc total: indicates exposure to HBV, does not distinguish acute from chronic infection or active infection from resolved infection.
Anti-HBc IgM: indicates recent infection or chronic infection with a flare of activity (by definition this will be the only positive marker during the window period of acute HBV infection).
HBeAg: typically indicates higher viral load and overall greater level of infectivity to others.
Anti-HBe: typically indicates a degree of immune suppression of HBV infection and a lower level of infectivity.
HBV DNA: used to monitor the level of viral replication in patients on treatment.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies are not used in the diagnosis of acute or chronic hepatitis B although abdominal imaging may be used to rule out alternative causes for abnormal liver chemistry studies such as biliary obstruction or malignancy. Additionally, some patients with chronic hepatitis B require routine screening for hepatocellular carcinoma which can be done with abdominal ultrasound, CT or MRI.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

If the clinical presentation suggests acute hepatitis B, the two most useful clinical tests are HBsAg and anti-HBc IgM. If both these tests are negative, then the patient does not need further testing as this rules out acute hepatitis B infection.

In the patient being evaluated for chronic liver disease (e.g., ALT < 250 U/L or unexplained cirrhosis), there is no value in checking anti-HBc IgM as this test is only used to diagnose acute hepatitis B or a clinically significant flare of chronic hepatitis B. Nonetheless, resources are often wasted on checking acute hepatitis panels in patients without evidence of acute hepatitis.

If patients are being followed for chronic hepatitis B, they should have ALT and HBV DNA checked periodically, at least every 6-12 months, since patients may evolve between different phases that do require treatment.

When patients have loss of HBsAg and gain anti-HBs, they no longer need monitoring of hepatitis B tests unless they are treated with immunosuppressive agents.

III. Default Management.

Evaluate the cause and extent of liver injury according to testing above.
Monitor for acute liver failure based on loss of liver synthetic function and the presence of encephalopathy. If both are present, patient requires immediate hepatology consultation and/or referral to a liver transplant center.
Rule out secondary viral (hepatitis D), extrahepatic manifestations.
Supportive care to alleviate and stabilize symptoms.
Non-urgent referral to hepatologist for ongoing monitoring and treatment. This includes preventative care.
Identification and evaluation of household contacts and sexual contacts with vaccination of those without evidence of infection or immunity.

A. Immediate management.

Immediate management for acute HBV infection is supportive care:

Judicious IV fluids for poor PO intake, using either normal saline or lactated Ringers. Monitor urine output. Excessive hydration should be avoided to reduce the risk of cerebral edema, a major cause of death in acute liver failure.
Antiemetics for nausea.
Discontinue previous treatments/medications that are hepatotoxic.
Avoid sedating or other CNS altering medications.
Limit acetaminophen to 2 grams per day. Avoid NSAIDS.
Liver ultrasound with doppler to rule out anatomic/vascular processes.
Rule out other viral hepatitis including HAV, HCV, HDV, HIV.

For healthcare workers exposed or possibly exposed to HBV, post-exposure prophylaxis is indicated only if the person has not been vaccinated, or is a “non-responder” to previous vaccination (anti-HBs <10 mIU/mL). Treat with HBIG once within 24 hours of exposure if the source is HBsAg positive. Give a full vaccination course to those not previously vaccinated and repeat vaccination course to those that are nonresponders.

B. Physical Examination Tips to Guide Management.

Vital signs to look for the presence of fever, hypotension, tachycardia which may indicate bacterial infection.
Mental status exam and examine for the presence of asterixis to identify hepatic encephalopathy. The presence of altered mentation suggests acute liver failure in the patient with acute hepatitis B or hepatic encephalopathy in the patient with chronic hepatitis B and cirrhosis.
Abdominal exam for a fluid wave or bulging flanks suggesting the presence of ascites.
Other clinical findings suggestive of advanced liver fibrosis or cirrhosis including caput medusa, gynecomastia, spider angiomata, palmar erythema.
Skin exam to monitor presence of jaundice or bruising, which may indicate worsening liver synthetic function.
Urine output and hematuria which may indicate acute renal failure due to pre-renal state or glomerulonephritis.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

AST, ALT, total bilirubin, alkaline phosphatase – twice daily in the acute setting until stable, then daily thereafter until discharge. Periodic monitoring while undergoing treatment.
PT, PTT, INR – twice daily in the acute setting until stable, then daily thereafter until discharge. Periodic monitoring while undergoing treatment.
BUN/creatinine/Urinalysis – upon admission. Periodic monitoring thereafter to screen for glomerulonephritis.
CBC – upon admission, and daily thereafter if concerns for bleeding.

Chronic hepatitis B is categorized into four phases based on the virus activity (HBV DNA level as a surrogate marker) and the patient’s immune response to the virus activity (ALT and liver histology as surrogate markers). Patients may evolve through some or all phases with variable duration. See Table II.

Chronic hepatitis B categorized into four phases

In the immune tolerant phase, viral replication is high with little or no inflammatory response. HBeAg seroconversion (loss of HBeAg, development of anti-HBe) occurs infrequently at this stage. Patients transition to the immune active phase with increasing likelihood over time.

In the immune active phase, viral replication is high and is associated with an inflammatory response and liver injury. HBeAg seroconversion (loss of HBeAg, development of anti-HBe) marks transition from this phase to the inactive phase in 8-15% of adults per year but rarely in children or immunocompromised patients.

In the inactive carrier phase, viral replication is low with little or no inflammatory response. Up to 20% of patients in this phase will reactivate due to loss of immunologic control by the host and/or use of immunosuppressive drug therapy.

In the immune reactivation phase, viral replication is high with inflammatory response and liver injury.

Resolution of chronic hepatitis B (clearance of HBsAg, development of anti-HBs) occurs in 0.5% of inactive carriers per year.

D. Long-term management.

Progression to cirrhosis occurs in up to 20% of patients with untreated chronic hepatitis B. Annual incidence of hepatic decompensation is 5-8% and hepatocellular carcinoma is 2-4% in patients with cirrhosis. Rates of cirrhosis and hepatocellular carcinoma (HCC) increase substantially with increased HBV DNA level, ALT levels, HBeAg positivity, and genotype C. Additional risk factors for HCC include advanced age, male gender, immunocompromised state, concomitant additional viral infection (HCV, HDV, HIV), alcohol use and metabolic syndrome. Furthermore, the risk of HCC is higher in patients from Sub-Saharan Africa, positive family history, and smoking.

All patients with cirrhosis should be screened for hepatocellular carcinoma with ultrasound every 6-12 months. Additionally, some high risk populations with chronic hepatitis B should be screened even in the absence of cirrhosis. These populations include Asian men over 40 years old, Asian women over 50 years old, African men and women over 20 years old and persistent ALT elevation with HBV DNA level >2,000 IU/mL, and patients with a positive family history of HCC.

Treatment with antiviral therapy is recommended in patients with chronic hepatitis B in the immune active phase with elevated HBV DNA levels (>2,000 IU/mL if HBeAg negative, >20,000 IU/mL if HBeAg positive) and ALT ≥2 ULN. Patients with cirrhosis and HBV DNA >2,000 IU/mL should be treated regardless of ALT level. If patients do not meet these cutoff criteria, antiviral therapy should still be considered in older patients, those with a family history of HCC, presence of extrahepatic manifestations, or prior treatment.

Treatment with antiviral therapy is generally not recommended for patients with immune tolerant chronic hepatitis B. However, patients should have labs checked every 6 months to monitor for evidence of activation. Additionally, in spite of normal ALT levels, patients should be treated with antiviral therapy if there is evidence of necroinflammation or fibrosis if a liver biopsy is obtained.

There are currently six medications approved for use in the United States. Choice of antiviral agent is driven by side effect profile, co-morbidities, prior therapy exposure, HBV genotype, costs, and pregnancy state.

Goals of antiviral therapy are HBeAg seroconversion (if HBeAg positive at initiation of treatment), HBsAg loss, and suppression of HBV DNA. All patients with cirrhosis should continue treatment indefinitely. Patients without cirrhosis can consider discontinuation 12 months after achieving the above mentioned goals. However, the risk for seroreversion or recurrent viremia persists and patients need to be monitored every 3 months for at least one year after discontinuation of antiviral therapy.

Finally, patients with chronic HBV infection and decompensated cirrhosis or hepatocellular carcinoma should be referred to a liver transplant center for ongoing care.

E. Common Pitfalls and Side-Effects of Management

Interferon is not commonly used due to its side effects including, but not limited to, depression, bone marrow suppression, activation of autoimmune disorders, and the risk of further decompensation in patients with cirrhosis.

The nuceoside/nucleotide analogues approved for use in the United States are lamivudine, adefovir, telbivudine, entecavir, tenofovir. The most commonly used antiviral therapy used now are entecavir and tenofovir as the others have been show to develop resistance with time. These drugs are administered orally. Brief periods of discontinuation are sometimes necessary for hospitalized patients unable to take oral medications. Treatment should be resumed as soon as possible when patients are able to take oral medications. The doses of tenofovir and entecavir should be adjusted for renal insufficiency (GFR < 50%). Refer to the package inserts for current specific guidance.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management for acute HBV infection.
Nucleoside/nucleotide analogues require GFR dependent dose reductions (please speak with your pharmacist).