Hepatobiliary Conditions

Learning Objectives

Describe populations that should be screened for hepatitis B and C virus.
Summarize appropriate intervals at which liver ultrasound should be performed for patients with hepatitis B and C virus who are at risk of hepatocellular carcinoma.
Outline diagnostic criteria for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
Discuss appropriate NAFLD and NASH treatments.
Obtain paracentesis on all patients with clinically apparent new-onset ascites.
Obtain diagnostic upper endoscopy on all patients with newly diagnosed cirrhosis of the liver.
Distinguish acute cholecystitis from common duct stones and acute cholangitis using history, physical examination, laboratory test, and imaging study results.
Discuss whether early or delayed cholecystectomy is preferred for patients with acute cholecystitis.

Key Practice Recommendations

Patients with suspected chronic hepatitis C virus (HCV) should be tested for HCV antibody and if positive, have quantitative HCV RNA and HCV genotype testing.
Advise weight loss and long-term physical activity as first-line interventions for patients with nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis, regardless of the severity of their liver disease.
Perform abdominal paracentesis and ascitic fluid analysis on all patients who have clinically apparent new-onset ascites.
Recommend diagnostic upper endoscopy to screen for varices for all patients with cirrhosis.
Recommend early (less than 72 hours of diagnosis) cholecystectomy for patients who have acute cholecystitis.
Arrange for urgent biliary decompression in patients with acute cholangitis who do not improve after 24 hours of antibiotic therapy or who have signs of septic shock.

Resources

Strength of evidence: SORT C
Source: Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(9):1335-1374.

Web site: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Diagnosis_of_HEP_C_Update.Aug%20_09pdf.pdf
Strength of evidence: SORT B
Source: Neuschwander-Tetri BA. Lifestyle modification as the primary treatment of NASH. Clin Liver Dis. 2009;13(4):649-665 [Review].

Web site: http://www.ncbi.nlm.nih.gov/pubmed/19818311
Strength of evidence: SORT C
Source: Runyon BA; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. 2009;49(6):2087-2107. AHRQ/National Guideline Clearinghouse

Web site: http://www.guideline.gov/summary/summary.aspx?doc_id=14887
Strength of evidence: SORT C
Source: Garcia-Tsao G, Sanyal AJ, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. Erratum in Hepatology. 2007;46(6):2052.

Web site: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Prevention%20and%20Management%20of%20Gastro%20Varices%20and%20Hemorrhage.pdf
Strength of evidence: SORT A
Source: Gurusamy KS, Samraj K, Fusai G, et al. Early versus delayed laparoscopic cholecystectomy for biliary colic. Cochrane Database Syst Rev. 2008;(4):CD007196; Siddiqui T, MacDonald A, Chong PS, et al. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a meta-analysis of randomized clinical trials. Am J Surg. 2008;189(1):40-47. Cochrane Collaboration and published trials

Web site: http://www2.cochrane.org/reviews/en/ab007196.html; http://www.ncbi.nlm.nih.gov/pubmed/18070735
Strength of evidence: SORT C/evidence grade Ib
Source: Williams EJ, Green J, Beckinham I, et al; British Society of Gastroenterology. Guidelines on the management of common bile duct stones (CBDS). Gut. 2008;57(7):1004-1021.

Web site: http://gut.bmj.com/content/57/7/1004.full.html

AAFP FP Essentials™ Approved as CME Clinical Content

This activity, FP Essentials™, has been reviewed and is acceptable for up to 60 Prescribed credit(s) by the American Academy of Family Physicians. AAFP accreditation begins June 1, 2010. This activity conforms to the AAFP criteria for evidence-based CME clinical content. Term of approval is for two year(s) from this date with the option of yearly renewal. Each monograph is approved for 5 Prescribed credit(s). Credit may be claimed for 2 years from the date of each monograph.

The evidence-based CME for this activity was based on a current clinical question that identifies gaps in learners’ knowledge, competency and/or performance in medical practice as identified in the current evidence available at the time this activity was approved. Since clinical research is ongoing and new evidence to supporting practice improvement is constant, the AAFP recommends that learners verify sources and review these as well as practice recommendations prior to implementation into practice.

Author Information

Doug Neef, MD, is an associate director at the Via Christi Family Medicine Residency Program in Wichita, Kansas. He also is a clinical assistant professor in the department of family and community medicine at the University of Kansas School of Medicine-Wichita, where he teaches residents and medical students. He completed a family medicine residency and was in private practice for 11 years before joining the Via Christi faculty.

Tracy Williams, MD, is a clinical assistant professor in the family and community medicine department at the University of Kansas School of Medicine-Wichita and an associate program director at the Via Christi Family Medicine Residency Program, Wichita. Dr Williams completed a family medicine residency and an obstetrics fellowship.

Scott Stringfield, MD, is an associate director of the Via Christi Family Medicine Residency Program as well as a volunteer clinical assistant professor with the department of family and community medicine at the University of Kansas School of Medicine-Wichita. After completing a family medicine residency, he spent 8 years in private rural practice before joining the residency program.

G. Marcus Stephens, DO, is a clinical assistant professor of family medicine at the University of Kansas School of Medicine-Wichita. He is the associate director of Via Christi Family Medicine Residency Program and the osteopathic program director and clinic medical director. He completed a family medicine residency and was in private practice for 16 years before joining the Via Christi faculty.

Disclosure: According to AAFP policy, authors must disclose all associations with proprietary entities that may have a direct relationship to the subject matter of their manuscript. The authors and staff have returned disclosure forms indicating that they have no such affiliation or financial interest to disclose. The AAFP uses an anonymous peer review process to evaluate the content of this activity. This process ensures a clear resolution of any potential conflicts of interest, and guarantees the fairness and balance of the content.

Foreword

With all our concern about heart disease, cancer, and the obesity epidemic, we sometimes forget that disorders of the hepatobiliary system are also major causes of disability and death. As pointed out in this FP Essentials™, cirrhosis is the 5th leading cause of death in middle-age Americans, and the 12th most common cause of death overall. Perhaps more striking is that obesity-related nonalcoholic liver disease, a condition that was barely discussed a few years ago, is now the most common liver disorder in the United States and it is ultimately fatal in 1 in 10 individuals.

And, of course, viral hepatitis is common, too—but more common than many of us realize. Indeed, the World Health Organization estimates that 2 billion individuals worldwide (almost 1 in every 3 on the planet) have been infected with the hepatitis B virus. Last but not least, biliary stone disease is an everyday problem that we all see in our practices. For those of us who reach old age, nearly all will have detectable gallstones.

The authors of this FP Essentials™ have put together a review of current thinking about each of the aforementioned disorders—viral hepatitis, nonalcoholic steatohepatitis, cirrhosis, and biliary stone disease. They review current diagnostic and management approaches to each of these conditions, and provide a number of useful practice recommendations from national and international expert groups. I found the content of this issue to be most informative, and I hope you will, too.

Barry D. Weiss, MD, FAAFP, Medical Editor
Professor of Family and Community Medicine
University of Arizona College of Medicine, Tucson

Preface

Conditions of the liver and biliary tree affect millions of individuals in the United States and worldwide. All age groups are affected by these conditions, and they can result from a wide variety of etiologies, many of which are incompletely understood.

The initial symptoms often are nonspecific, and sometimes symptoms are absent during the early course of liver disease. Thus, when incidental abnormalities of liver function or structure are found on routine laboratory tests or imaging studies, detection of these conditions requires a high degree of suspicion and a logical diagnostic approach. This approach also is necessary when monitoring disease progression and response to treatment later, when the issues associated with these hepatobiliary conditions can become chronic, debilitating, and or even life-threatening.

This FP Essentials™ provides updates on 4 of the most common hepatobiliary conditions encountered in family medicine: viral hepatitis, nonalcoholic fatty liver disease, cirrhosis, and biliary stone disease. The discussion focuses on the optimal diagnostic and management strategies based on the best available current evidence and expert recommendations. New approaches and trends are emphasized.

SECTION ONE

New Strategies in the Diagnosis and Management of Chronic Viral Hepatitis

Hepatitis C Virus

Hepatitis C virus (HCV) affects an estimated 180 million individuals worldwide and 3.2 million US individuals. A prevalence of 1% to 2% in the American population makes HCV the most common chronic blood-borne infection, but in certain high-risk groups (Table 1) the prevalence is as high as 70% to 90%.1

Table 1

Risk Factors for HCV Infection

Major risk factors

Current or past (even remote, single episode) injection drug use

HIV infection

Receipt of clotting factor concentrate before 1987

Blood transfusion or organ transplantation before 1992

Treatment with hemodialysis

Being the child of a mother infected with HCV^a

Needle-stick or mucosal injury with potential exposure to HCV-positive blood

Other factors that slightly increase risk

Having multiple sexual partners

Being the sexual partner of an HCV-infected individual

Intranasal cocaine use with shared equipment or paraphernalia

^aIn children, standard HCV antibody testing should be delayed until age 18 months to avoid false-positive results from maternal antibodies in the child’s circulation. HCV RNA testing can be performed as early as ages 1 to 2 months.

HCV = hepatitis C virus.

Information from National Digestive Diseases Information Clearinghouse. Chronic hepatitis C: current disease management. Bethesda, MD: NDDIC; November 2006. NIH Publication No. 07–4230. Available at http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/chronichepc.pdf.

Although the incidence is declining, approximately 35,000 new HCV infections occur annually in the United States. Approximately 80% of those with acute infection go on to develop chronic HCV infection, which in the United States is the leading reason for liver transplantation and causes at least 12,000 deaths each year.1,2

Case 1. Carl is a 44-year-old construction worker. He occasionally injected drugs in the past but denies any current drug use. Routine blood test results showed mildly elevated transaminase levels. He smokes 1 to 2 packs/day of cigarettes and drinks at least 2 beers/day. Carl denies any recent or chronic illnesses.

Who Should Be Tested?

A 2004 review by the US Preventive Services Task Force was inconclusive about the benefits of HCV testing in high-risk populations.3 However, more recent recommendations (eg, those from the American Association for the Study of Liver Diseases [AASLD], which are endorsed by the Infectious Diseases Society of America) endorse such testing for patients who are at high risk.4

Tests

The 2 principal diagnostic tests for HCV, which also are used to determine the need for treatment, are anti-HCV antibody tests and molecular tests for HCV RNA (viral load). After infection, anti-HCV antibodies are not detectable for 8 to 12 weeks, whereas HCV RNA can be detected as early as 2 weeks after infection.4

Antibody Tests.

These tests are typically enzyme immunoassays. They test for multiple HCV antigens and, thus, are highly sensitive and highly specific (greater than 99%). As a result, confirmatory testing with immunoblot assays is no longer routinely performed.3 However, antibody test results can be falsely negative in patients who are immunocompromised and do not produce measurable quantities of antibody.

Molecular Tests.

These tests use polymerase chain reaction or transcription-mediated amplification techniques to detect HCV RNA; they can be qualitative or quantitative. Quantitative tests are now measured in World Health Organization HCV international units rather than number of viral copies. The lower limit of detection of current tests is 10 to 50 IU.4

Interpreting Results

A positive HCV antibody test result reliably indicates HCV infection but does not determine whether the infection is acute, chronic, or recovered. Thus, after a positive antibody test result for HCV, a quantitative molecular test should be obtained to detect the presence of HCV RNA. Patients positive for HCV antibodies and HCV RNA have an acute or chronic infection, depending on the clinical context.4 Interpretation of discordant results is shown in Table 2.

Table 2

Interpretation of Discordant HCV Test Results

Anti-HCV Antibody	HCV RNA (Viral Load)	Interpretation
Positive	Negative	Resolved infection
		Acute infection with low viral load
Negative	Positive	Early infection (antibodies not yet detectable)
		Chronic infection with impaired immune response

HCV = hepatitis C virus.

Information from Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.

Genotype Testing

Hepatitis C virus genotyping should be obtained after an acute or chronic infection is confirmed. Genotype 1 is most common in the United States, followed by genotypes 2 and 3. Genotypes 4 to 6 typically are encountered in minority ethnic groups.5 Infection with more than 1 genotype is uncommon.

Genotype testing is useful for predicting the likelihood of treatment response and the optimal treatment dosage and duration. More than 80% of patients infected with genotypes 2 and 3 achieve sustained virologic response to standard 6-month therapy. However, with genotype 1, sustained virologic response varies by ethnicity (approximately 50% of whites and 30% of blacks benefit from therapy).4

Liver Biopsy

Although not always necessary for diagnosis, biopsy can provide information on disease severity and features predicting treatment response.6 On biopsy, disease severity is based on scoring systems that consider grade (extent of inflammation) and stage (fibrosis or cirrhosis) of liver damage. In general, patients with the more susceptible genotypes and greater inflammation and fibrosis on biopsy are most likely to benefit from treatment. Biopsy also can identify other liver conditions, especially steatosis or excess hepatocellular iron, that can negatively influence disease progression and treatment response.7,8

Liver biopsy can be dangerous, is expensive, and requires expertise for performance and interpretation of results; therefore, it should only be used when the results will contribute to decisions about therapy after considering such factors as infection duration, viral genotype, indices of hepatic function, and patient perspectives.4

Tests other than biopsy are being investigated for accuracy in identifying the presence and degree of fibrosis and cirrhosis.9 These tests include standard imaging tests and transient elastography, a noninvasive measure of liver stiffness. Elastography is available in other countries but is not yet approved by the Food and Drug Administration. Elastography can be unreliable in obese patients and those with acute hepatitis.10

Medical Treatment

The two major virologic predictors of treatment success are viral genotype and pretreatment viral load.1,4 Patients with genotypes 2 and 3 and viral loads less than 800,000 IU/mL might have better response to therapy.

Standard Therapy.

Standard therapy for chronic HCV is the combination of a pegylated interferon alfa and ribavirin. This regimen is based on 3 large trials of patients with genotype 1, the most common type in the United States. Less information is available about therapy for genotypes 2 and 3, and limited information exists about genotypes 4 to 6.

Therapy duration is based on genotype and initial virologic response, and dosing should be based on patient weight.4 The measures of response to therapy are biochemical (transaminase levels), virologic (HCV RNA levels), and histologic (biopsy evidence of inflammation and fibrosis).

New drugs and treatment strategies using protease inhibitors and polymerase inhibitors that directly interfere with HCV replication at the genetic level are being developed, but toxicity currently limits use of these therapies. Two protease inhibitors are currently in clinical trials for this indication, but none has yet been approved. As the treatment regimens for chronic HCV are complex and constantly changing, many family physicians prefer to refer HCV patients to a subspecialist, at least for therapy initiation.

Virologic Cure.

Virologic cure is defined as a sustained virologic response (ie, the absence of HCV RNA 24 weeks after therapy discontinuation using a polymerase chain reaction assay with a lower limit of detection of less than 50 IU/mL). A sustained virologic response occurs in approximately half of patients.4 A rapid virologic response, defined as undetectable HCV RNA after 4 weeks of treatment, predicts a high likelihood of achieving sustained virologic response after therapy completion. On the other hand, a failure to achieve a complete early virologic response, defined as the complete absence of HCV RNA at week 12 of therapy, is an accurate predictor of nonresponse; therapy is typically discontinued if there is no early virologic response. Consider referral to a hepatology subspecialist for individualized treatment.

Initiation.

The decision to initiate therapy is based on a variety of considerations. The AASLD provides guidelines describing 3 classes of patients: those for whom therapy is indicated, those for whom it is contraindicated, and those requiring individualized decisions about therapy.4 Of importance, transaminase levels are not used to determine treatment eligibility.

Rather, treatment is typically indicated and should be considered for adults with a measurable viral load, significant hepatic fibrosis, compensated liver disease (bilirubin level 1.5 mg/dL or greater; albumin level 3.5 g/dL or greater; platelet level 75,000/mm³ or greater; and no coagulopathy, hepatic encephalopathy, or ascites), and who can adhere to treatment requirements. Contraindications to treatment are shown in Table 3. Case-specific decisions should be made for patients who have not benefited from prior treatment or have chronic renal disease, are younger than 18 years, or have HIV infection or acute HCV infection.4

Table 3

Contraindications to Standard Therapy for HCV Infection

Standard therapy with pegylated interferon alfa-2a and ribavirin typically is considered inadvisable for patients with the following characteristics:

Clinical decompensated cirrhosis because of HCV infection

Kidney, liver, heart, or other solid organ transplant

Pregnancy or inability to practice birth control

Contraindications to pegylated interferon:

Severe depression or other neuropsychiatric conditions

Active substance or alcohol abuse

Autoimmune disease not well controlled

Bone marrow compromise

Contraindications to ribavirin:

Severe anemia (hemoglobin level lower than 11 g/dL)

Renal dysfunction

Coronary artery disease

Cerebrovascular disease

HCV = hepatitis C virus.

Adverse Effects.

Adverse effects occur in almost all patients who are treated with pegylated interferon alfa-2a plus ribavirin, with 10% to 14% of patients in some trials discontinuing therapy because of adverse effects.11 The most common of these adverse effects are flu-like symptoms, such as fatigue, headache, and fever, which are experienced by more than 50% of patients. Psychiatric symptoms, especially depression, irritability, and insomnia, are reported by 20% to 31% of patients.1,4

Dosage reduction is commonly necessary because of abnormalities in laboratory test results, especially neutropenia and anemia. The lowest hemoglobin levels typically occur after 6 to 8 weeks of therapy.4 Interferon might induce autoimmune disorders, such as thyroiditis. Ribavirin can cause hemolytic anemia and has been linked to fetal mortality and abnormalities in animal studies.4 Ribavirin is cleared by the kidneys, so it should also be used with extreme caution in patients with renal disease.

Additional Therapeutic Concerns

Every effort must be made to avoid additional hepatic damage. Thus, HCV-infected patients should be advised to completely abstain from or severely restrict alcohol intake.12 Obesity can enhance progression of fibrosis and impair response to therapy, so appropriate weight loss should be encouraged.13

The AASLD recommendations state that patients with chronic HCV infection who lack antibodies to hepatitis A or B virus should be immunized to prevent these infections.4 Prescription drugs should be restricted to those without hepatic toxicity, and patients should be cautioned about the use of nonprescription drugs and herbal remedies. Table 4 lists drugs that could be hepatotoxic. Although some herbal remedies have been associated with fulminant hepatitis, 40% of patients in one treatment trial had used some type of herbal remedy, especially silymarin (milk thistle extract [Silybum marianum]), a flavonoid thought to have a hepatoprotective effect.14 A large prospective trial of patients

Table 4

Drugs Commonly Implicated in Hepatotoxicity

Prescription drugs

Acetaminophen

Amoxicillin

Amiodarone

Chlorpromazine

Ciprofloxacin

Diclofenac

Erythromycin

Fluconazole

Isoniazid

Methyldopa

Oral contraceptives

Rifampin

Statins

Valproic acid

Herbal preparations

Senecio/Crotalaria (bush tea)

Germander (Teucrium)

Chaparral (Larrea tridentata)

Chinese herbs (Lycopodium serratum, Ephedra equisetina also known as ma huang)

Illicit drugs

Ecstasy

Cocaine

Note: This is not a complete list, as there are hundreds of drugs with potential hepatotoxicity. Consult appropriate references before prescribing any drug to a patient with liver disease.

Information from Mehta N, Ozick L, Gbadehan E. Drug-induced hepatotoxicity. eMedicine. WebMD. 2010. Available at http://emedicine.medscape.com/article/169814-overview.

with advanced HCV liver disease reported significantly reduced progression of hepatic damage in those who drank 3 or more cups/day of coffee.15

Counseling and Prevention

Patients with HCV infection should be counseled on measures to prevent infecting others. Measures to prevent transmission of HCV mainly target bloodborne infection (Table 5).1,4,16 Patients with HCV and cirrhosis are at increased risk for hepatocellular carcinoma (HCC) and should undergo ultrasound screening for HCC at 6- to 12- month intervals.17

Table 5

Measures to Prevent HCV Transmission

Avoid sharing toothbrushes and dental or shaving equipment

Cover any bleeding wound to prevent blood contact

Stop illicit drug use

If continuing illicit drug use, avoid reusing/sharing syringes, needles, or other paraphernalia; clean every injection site with a new alcohol swab; dispose of syringes and needles safely

Do not donate blood, organs, tissue, or semen

Minimize risk of sexual transmission^a

^aRisk of sexual transmission is low (1% to 5%) in monogamous relationships but higher in individuals who have multiple sexual partners. Barrier protection may not be indicated in monogamous couples, but others should always practice safer sex.

HCV = hepatitis C virus.

Information from Centers for Disease Control and Prevention; Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR-11):1-94.

Case 1, cont’d. Results of the quantitative test results show a viral load of 400,000 IU/mL of hepatitis C virus genotype 1. Because Carl is in good health and has no contraindications to therapy, you think he might be a good candidate for treatment and refer him to a hepatology subspecialist.

Hepatitis B Virus

An estimated 1.25 million individuals in the United States are positive for hepatitis B surface antigen (HBsAg). Chronic hepatitis, cirrhosis, and/or HCC develop in 15% to 40% of these individuals.18 The risk of chronic hepatitis is influenced by the age of the individual and mode of acquisition of acute hepatitis B virus (HBV).19 Approximately 90% of infections acquired by perinatal transmission, most common in southeast Asia and China, result in chronic hepatitis.20 On the other hand, chronic hepatitis develops in only approximately 5% of HBV infections acquired at an older age, typically percutaneously or by sexual contact, which are the most common routes of infection in the United States.20

Approximately 10% to 15% of individuals with HBV also are infected with HCV (often because of injection drug use), and approximately 10% also are infected with HIV, with higher rates of coinfection in areas in which both conditions are endemic (Table 6).21,22 Coinfection with hepatitis D virus is common in South American and Mediterranean endemic areas, but uncommon in the United States.

Table 6

High-Risk Groups That Should Be Screened for HBV Infection

Individuals born in areas with 2% or greater prevalence of HBV^a

Children of HBsAg-positive immigrants

Nonimmunized US-born children of families from high-prevalence areas

Household and sexual contacts of HBsAg-positive individuals

Injection drug users (any, even remote history)

Individuals with a history of sexually transmitted disease or multiple sexual partners

Men who have sex with men

Prison (and similar facilities) inmates

Individuals with chronic transaminase level elevations

Individuals with HCV or HIV infection

Patients undergoing renal dialysis

Patients receiving immunosuppressive therapy

Pregnant women

^aAreas with a prevalence of 2% or greater include all countries in Asia and Africa; all countries in the South Pacific except Australia and New Zealand; all countries in the Middle East except Cyprus and Israel; all countries in Eastern Europe except Hungary; the Western European countries of Malta and Spain; the Latin American countries of Guatemala, Honduras, Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas of Bolivia, Brazil, Columbia, and Peru; the Caribbean nations of Antigua-Barbuda, Dominica, Granada, Haiti, Jamaica, Saint Kitts-Nevis, St. Lucia, and Turks and Caicos Islands. Also included are indigenous populations of Greenland, Alaska, and Northern Canada.

HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus.

Information from Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Childhood immunization has contributed to a decline of more than 80% in the number of acute HBV infections in the United States since 1991.22 The incidence in the United States is now only 1.6/100,000 per year.23 Nevertheless, chronic HBV infection continues to be a serious health problem, especially among immigrants from endemic areas.

Case 2. Robert is a 35-year-old man with a history of alcohol abuse and injection drug use. Results of routine laboratory tests show an elevated alanine aminotransferase (ALT) level that is just less than 2 times the upper limit of normal. He is asymptomatic and physical examination findings show he is healthy.

Natural History

The natural history of chronic HBV infection has 3 main phases (Figure 1). The immune-tolerant phase typically follows perinatal or childhood infection and is characterized by active viral replication (high levels of HBV DNA) with immune tolerance and, thus, minimal disease activity. Liver inflammation is minimal and transaminase levels typically are normal.20

Figure 1

Natural History of Chronic HBV Infection

HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus.

Reprinted from NIH Consensus Development Conference Statement on Management of Hepatitis B. 2008;25(2):8. Available at http://consensus.nih.gov/2008/hepbstatement.pdf.

After many years, patients progress to the immune-active phase, in which the increased immune response to HBV is shown by evidence of liver inflammation with elevated transaminase levels. Patients might also enter this phase directly by person-to-person transmission later in life. Those who remain in the immune-active phase for the longest time have the greatest risk of cirrhosis and HCC.

Many patients then transition to an inactive carrier state, with low levels of HBV DNA, reduced liver inflammation, and normalization of transaminase levels. However, up to 20% of patients in the inactive carrier state revert to the immune-active phase, so lifelong surveillance is recommended.20

For others, antibodies against the surface antigen (anti-HBs) develop, which typically indicates resolution of HBV. However, some of these patients might still have detectable levels of HBV DNA, a condition referred to as latent HBV.19

Testing

The most recent recommendations for high-risk groups that should be tested for HBV are summarized in Table 6.20,23,24 Testing should also be performed in patients with unexplained elevation of transaminase enzymes.

The HBsAg is the principal serologic marker of acute and chronic HBV infection. It appears 4 to 10 weeks after acute exposure to HBV and typically becomes undetectable 4 to 6 months after disease resolution. Persistence of HBsAg for more than 6 months defines chronic infection.

Testing for HBV involves measurement of HBsAg and of antibodies to the surface and core antigens. Interpretation of test results is shown in Table 7.

Table 7

Interpretation of HBV Serology Test Results

Serologic Test
HBsAg	Total Anti-HBc	IgM Anti-HBc	Anti-HBs	Interpretation
−	−	−	−	Never infected
+	−	−	−	Early acute infection; transient (up to 18 days) after vaccination
+	+	+	−	Acute infection
−	+	+	−	Resolving acute infection
−	+	−	+	Recovered from past infection and immune
+	+	−	−	Chronic infection
−	+	−	−	False-positive; past infection; low-level chronic infection; passive transfer to infant born to HBsAg-positive mother
−	−	−	+	Immune if anti-HBs concentration is 10 mIU/mL or greater; recent hepatitis B immune globulin administration

Anti-HBc = antibodies to hepatitis B core antigen; anti-HBs = antibodies to hepatitis B surface antigen; HBsAg = hepatitis B surface antigen; IgM = immunoglobulin M.

Reprinted from Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices. Part I: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):4. Erratum in MMWR Morb Mortal Wkly Rep. 2006;55 (6):158-159. MMWR Morb Mortal Wkly Rep. 2007;56(48):1267. Also available at http://www.cdc.gov/mmwr/PDF/rr/rr5416.pdf.

Case 2, cont’d. Because of the elevated ALT level and history of injection drug use, Robert is screened for hepatitis B virus (HBV) and other blood-borne conditions. He tests positive for hepatitis B surface antigen (HBsAg) and total antibodies to hepatitis B core antigen (anti-HBc), but negative for immunoglobulin M anti-HBc and antibodies to HBsAg. Based on the information in Table 7, you conclude that Robert has chronic HBV infection.

Medical Treatment

The decision to treat HBV with drugs depends primarily on the degree of viral replication and hepatic inflammation. A high rate of viral replication is demonstrated by high levels of HBV DNA and the presence of the early antigen (HBeAg). Hepatic inflammation is shown by high alanine aminotransferase levels or hepatitis on liver biopsy.

Based on the parameters previously discussed, the algorithm in Figure 2 outlines initiation of treatment designed to suppress viral replication, minimize or prevent hepatic damage, decrease the risk of cirrhosis or HCC, and prevent transmission of HBV.20,24 In addition to the treatment indications shown in Figure 2, therapy also is indicated for patients with acute hepatic decompensation, cirrhosis with clinical complications, or reactivation of chronic HBV after chemotherapy or other forms of immunosuppression.

Figure 2

Algorithm for Chronic HBV Infection Treatment

Note that this algorithm assumes the patient is positive for hepatitis B surface antigen. Note also that other scenarios, not portrayed here, are possible.

ALT = alanine aminotransferase; HBeAg = hepatitis B early antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; ULN = upper limit of normal.

Information from Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):661-662.

Seven therapeutic agents have been approved for treatment of chronic HBV in adults and include interferon alpha (pegylated and conventional) and nucleoside/nucleotide analogues, including lamivudine, adefovir, entecavir, tenovir, and telbivudine. The indications and regimens for these drugs are complicated.20

Combinations of these drugs have not demonstrated higher rates of sustained response than monotherapy, though a second drug often is added if HBV DNA is still detectable after 6 to 12 months of monotherapy. Pegylated interferon alfa therapy is administered weekly for 6 to 12 months, but seroconversion (development of antibody to HBsAg) might not take place until several months after completing therapy.25 Nucleosides/tides need to be taken for years and should be continued for at least 6 months after seroconversion but are often limited by development of viral resistance. Renal function must be monitored throughout therapy.

Counseling and Prevention

General Measures.

General measures for patients with chronic HBV infection include avoiding exposure to alcohol and hepatotoxic drugs. Patients should also be tested and treated for other etiologies of liver disease. They should receive hepatitis A immunization if not already immune. Infants of HBsAg-positive mothers require treatment with hepatitis B immune globulin in addition to routine immunization against HBV. No dietary modifications or supplements have demonstrated hepatic protection in HBV infection.

Ultrasound Screening for HCC.

Screening for HCC is recommended at 6- to 12-month intervals for all HBV carriers who are at high risk for this malignancy (Table 8). If ultrasound is not available, periodic screening with alpha-fetoprotein can be considered, but it is less accurate than ultrasound.20

Table 8

Hepatitis B Virus Carriers Who Should Undergo Ultrasound Examination Every 6 to 12 Months to Screen for Hepatocellular Carcinoma

Asian men older than 40 years

Asian women older than 50 years

Africans older than 20 years

Patients with cirrhosis

Patients with a family history of hepatocellular carcinoma

Any carrier older than 40 years with persistent or intermittent ALT level elevation and/or HBV DNA level greater than 2,000 IU/mL

ALT = alanine aminotransferase; HBV = hepatitis B virus.

Information from Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):661-662.

Preventive Measures

Preventive measures to prevent the spread of HCV also apply to HBV, but the increased risk of HBV transmission means that household contacts and sexual partners of HBV-positive patients with negative HBV markers should also be immunized.20 Barrier contraception should be used with nonimmune sexual partners.

Case 2, cont’d. Further evaluation shows that Robert is positive for hepatitis B early antigen. However, the HBV DNA level is only 15,000 IU/mL and, as noted, the ALT level is less than twice the upper limit of normal. Based on the algorithm in Figure 2, Robert is not currently a candidate for HBV treatment. You plan to monitor serum HBV DNA and ALT levels every 3 to 6 months.

SECTION TWO

Nonalcoholic Fatty Liver Disease and Steatohepatitis

Case 3. Kelly is a 45-year-old woman taking metformin and pravastatin for type 2 diabetes, central obesity, hypertension, and hyperlipidemia. Laboratory test results are normal, apart from mild elevations of aspartate aminotransferase, alanine aminotransferase, and hemoglobin A1c. She denies (and her husband verifies) any alcohol or illicit drug use or history of tattoos, piercings, or recent unprotected sexual activity. She has no personal or family history of liver disease, but both parents were obese and had diabetes. Results of tests for viral hepatitis are negative. Ultrasound examination reveals diffuse fatty infiltration of the liver with no masses. Liver biopsy demonstrates nonalcoholic fatty liver disease with inflammation and fibrosis, consistent with nonalcoholic steatohepatitis.

Background

Nonalcoholic fatty liver disease (NAFLD) includes a range of histologic conditions from steatosis (fatty infiltration) to nonalcoholic steatohepatitis (NASH), the latter being an inflammatory condition that can progress to cirrhosis. Although underrecognized by physicians, NAFLD is the most common liver disease in the United States,26 with a prevalence of 17% to 33% in Western countries and up to 80% in morbidly obese individuals.27

Etiologies

The etiology of NAFLD is probably multifactorial, but the roles of obesity and insulin resistance are well recognized. Indeed, NAFLD is considered the hepatic manifestation of the metabolic syndrome.28 Non-obese patients might occasionally have NAFLD, but they exhibit clinical and laboratory findings similar to those seen in obese patients with diabetes.28 As the prevalence of obesity in the population rises, the incidence of NAFLD and NASH will continue to increase. Conversely, histologic improvements in NAFLD and NASH occur when body mass index is reduced.29

Insulin resistance is thought to be the initial pathologic change that results in the fatty accumulation (steatosis) seen in NAFLD. The fatty liver in NAFLD is then vulnerable to biochemical injury, particularly from oxidative stress. Although debate continues about whether cell injury causes inflammation or vice versa, both processes are involved in development of NASH.30

Several clinical factors predict the progression of NAFLD to the inflammatory condition of NASH. Obesity with a body mass index greater than 30 kg/m² is a strong predictor of progression, and hypertension and insulin resistance (independent of obesity) also are predictors.

Although NAFLD can have a benign course, approximately 25% of those who progress to NASH will ultimately develop cirrhosis and 30% to 40% of that subset will die from hepatic etiologies, such as liver failure or hepatocellular carcinoma over a 10-year time span.31,32 Four types (grades) of adult NAFLD are recognized based on the degree of inflammation and fibrosis seen in liver biopsy specimens (Table 9), and patients with NAFLD types 3 and 4 have the highest risk of progression to cirrhosis.32

Table 9

Histologic Types of Nonalcoholic Fatty Liver Disease

Type	Description	Significance
1	Simple steatosis	Early stage
2	Steatosis with lobular inflammation	Early stage
3	Steatosis, inflammation, and varying amounts of fibrosis	Risk of progression to cirrhosis
4	Steatosis, inflammation, balloon cells, hyaline, fibrosis	Highest risk of progression to cirrhosis

Information from Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413-1419.

Diagnosis

Patients with NAFLD/NASH typically are asymptomatic or have nonspecific gastrointestinal symptoms. These conditions usually come to clinical attention because of incidental findings on laboratory or imaging tests, especially elevated transaminase levels or fatty liver on ultrasound or computed tomography (CT) scan.33

Step 1. Exclude Alcohol as Etiology

In cases of incidental findings of elevated liver enzymes or fatty liver on ultrasound, the first step in diagnosing NAFLD or NASH is to exclude excessive alcohol intake, typically defined as more than 70 g/week of ethanol for women and more than 140 g/week for men.34 A standard drink (eg, can of beer, shot of straight alcohol, glass of wine) has approximately 10 g of ethanol.

Obtaining an accurate history of alcohol intake is challenging; many studies rely on patient reporting that is confirmed by family members. Because patient reports can be unreliable, attempts have been made to identify blood tests that can distinguish patients who engage in excessive drinking.

The most widely used test is one that measures gamma-glutamyl transferase (GGT) levels; it can be helpful because daily consumption of more than 80 g of alcohol causes elevation of GGT levels in approximately 60% of patients. However, GGT levels might be normal in patients who have higher rates of alcohol consumption, and might be elevated for other reasons (eg, use of prescription drugs, such as barbiturates and phenytoin). Thus, it is not a definitive test for alcohol use.

Although not as widely available as the GGT test, tests that measure transferrin levels—specifically, carbohydrate-deficient transferrin—are thought to be better for excluding alcohol use.35,36,37,38,39 Absence of an elevated transferrin level indicates lack of excessive alcohol ingestion.

Another useful indicator of alcohol consumption is the aspartate aminotransferase-alanine aminotransferase (ALT) ratio. This ratio is less than 1 in most NASH patients.40,41 NASH also can present with an isolated increase in the alkaline phosphatase level, although this finding is nonspecific.42,43

Step 2. Exclude Other Etiologies of Hepatitis

The second step in evaluating patients with elevated transaminase levels is to exclude causes of hepatitis, such as viral hepatitis (B, C, and D), hereditary hemochromatosis, Wilson disease, alpha₁-antitrypsin deficiency, and autoimmune hepatitis. After exclusion of these conditions, NAFLD accounts for approximately 90% of cases of elevated transaminase levels.44

Step 3. Imaging

The third step in diagnosing NAFLD is obtaining images to help confirm the diagnosis. Ultrasound is noninvasive, inexpensive, and widely available, and it does not expose the patient to ionizing radiation. However, it has limited accuracy for detection of steatosis when liver fat content is less than 30%, and NAFLD can be present when liver fat content is only 5% to 10%. Ultrasound also cannot always distinguish steatosis from fibrosis, so it is insufficient to differentiate between NAFLD and NASH.45

Computed tomography scan is superior to ultrasound in assessing the amount of steatosis present. It can objectively measure liver attenuation, which is low in steatosis, but most CT scanners are not appropriately calibrated for this assessment.45 Furthermore, the level of attenuation associated with the risk of progression to cirrhosis is not yet clear.46 Radiation exposure is another disadvantage of CT scans, especially for longitudinal monitoring of patients.

Magnetic resonance imaging study is superior to ultrasound or CT scan for measuring the amount and degree of fatty liver, making it the test of choice. However, there are concerns about cost and availability. Magnetic resonance spectroscopy is even more promising and is available on most commercial scanners, but requires significant expertise for interpretation.45

Step 4. Consider Liver Biopsy

Definitive diagnosis of NAFLD or NASH requires liver biopsy, which is invasive and carries risks. The decision to obtain the biopsy and the timing of the procedure should be individualized for every patient. However, in general, patients should be referred for liver biopsy if they have persistently elevated transaminase levels for which the etiology has not been definitively identified. Liver biopsy provides diagnostic information and guides treatment decisions. Furthermore, liver enzyme levels alone might not accurately reflect disease severity, as normalization of transaminase levels often occurs while NASH is still progressing.47

Treatment

Weight Loss

Ultimately, treatment of NAFLD/NASH must target the obesity and associated insulin resistance that are the etiologic bases of these conditions. Thus, the mainstay of therapy for NAFLD/NASH is promotion of weight loss. Weight loss combined with an increase in physical activity can improve liver enzyme test results, liver histology, serum insulin levels, and overall quality of life.48,49 It is reasonable to recommend that patients with NASH lose 7% to 10% of their body weight over 6 to 12 months by increasing physical activity and incorporating dietary modification.50,51

Rapid weight loss can exacerbate liver disease, so weight loss should be gradual, not exceeding 1.6 kg (3.5 lb)/week for adults.52 Adherence to dietary recommendations is typically poor, resulting in an average of only 3 to 4 kg (6.6 to 8.8 lb) weight loss after 2 to 4 years. Adherence to modifications in physical activity is equally poor.53 A simple recommendation to change diet or exercise is ineffective. More effective is the patient setting goals in collaboration with the physician as described in the 5 A’s Behavior Change Model.54

Bariatric Surgery

Although gastric bypass has been reported as a risk factor for development of NAFLD—based on previous experience with jejunoileal bypass surgery—benefits of newer forms of bariatric surgery appear to outweigh the risks. Indeed, bariatric surgery, including biliointestinal bypass and gastric banding procedures, has shown promise in treating NAFLD. Liver biopsies obtained at the time of surgery and repeated 1 year postoperatively showed a decrease in steatosis.55 However, no change in inflammation and fibrosis is noted, although a decrease in hepatic factors involved in fibrogenesis has been demonstrated after bariatric surgery.55 Another study showed that the baseline severity of insulin resistance helps predict which patients will benefit most from bariatric surgery, and which will have persistent severe steatosis 1 year postoperatively.56

However, despite promising preliminary results, a 2010 Cochrane review sought studies of bariatric surgery for NAFLD treatment that used any sort of randomized design: procedure versus no procedure, procedure versus sham procedure, or other randomized interventions. Investigators found no such trials and concluded that there is insufficient evidence to fully assess the benefits and harms of bariatric surgery as an effective NAFLD treatment.57

Drugs

Orlistat.

Orlistat (Xenical) blocks absorption of dietary triglycerides by reversibly inhibiting gastric and pancreatic lipases. It has been shown to improve glycemic control by causing weight loss. In a meta-analysis, patients treated with orlistat lost 2.9 kg (6.4 lb) and improved the diabetes control.58

When specifically evaluated for its effect on NASH, several case series and uncontrolled trials demonstrated favorable effects,53 but more recent randomized control trials failed to show enhanced weight loss, improved liver enzyme values, or improved histopathology results greater than were achieved with placebo when both groups received intensive dietary counseling.59,60 Therefore, any beneficial effect of orlistat on NAFLD/NASH beyond that attributable to weight loss is debatable. Orlistat is Food and Drug Administration (FDA)-approved only for obesity treatment.

Insulin-Sensitizing Drugs

Insulin-sensitizing drugs are of interest as NAFLD and NASH treatments because insulin resistance plays a role in development of these conditions. Studies of insulin-sensitizing drugs have involved thiazolidinediones (pioglitazone [Actos] and rosiglitazone [Avandia]) and metformin. The results of those studies are typically favorable, though not all studies have supported the benefit of these drugs for treating NAFLD and NASH.

For example, a double-blinded randomized placebo-controlled study of NASH patients with impaired fasting glucose or type 2 diabetes showed significant improvement in abnormal liver enzyme test results, increases in hepatic insulin sensitivity, and improved liver histology results in those treated with a hypocaloric diet plus pioglitazone for 6 months compared with diet alone.61

Similar findings were reported in nondiabetic patients randomized to a standard diet plus exercise plus placebo or pioglitazone (30 mg) for 12 months. Patients who received pioglitazone had increased weight loss; lower serum glucose, hemoglobin A1c, and transaminase levels; and improved hepatocellular injury and fibrosis.62

However, in another study that compared pioglitazone, vitamin E, and placebo for treatment of nondiabetic patients with NASH, the benefit of pioglitazone was less clear. This study randomized 247 nondiabetic patients with biopsy-confirmed NASH to pioglitazone, vitamin E, or placebo for 96 weeks. Vitamin E therapy was associated with a significant improvement in the nonalcoholic steatosis score (43% for vitamin E versus 19% for placebo), but although pioglitazone showed a trend toward reduction in the score (34% versus 19%), the degree of reduction was not statistically significant.63

Another thiazolidinedione, rosiglitazone, was evaluated in the Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. In this study, 63 patients were randomized to receive rosiglitazone or placebo for 1 year. All patients also participated in intensive lifestyle modification. More patients in the rosiglitazone group showed a reduction in steatosis compared with patients in the placebo group (47% versus 16%), and rosiglitazone recipients were more likely than placebo-treated patients to experience normalized transaminase levels (38% versus 7%). However, histologic grading of liver biopsy specimens showed no improvement,64 again calling into question the benefit of these insulin-sensitizing drugs for NASH treatment. In addition, use of rosiglitazone has been severely restricted by the FDA to only patients with uncontrolled type 2 diabetes unresponsive to other drugs who have been provided thorough safety information and whose providers have enrolled in the FDA’s restricted access program. This restriction was implemented in response to data that showed rosiglitazone increased the risk of cardiovascular events.65

Several trials of metformin in diabetic and nondiabetic patients with NAFLD and NASH have mostly reported positive results, but again, the heterogeneity of the trial results and involvement of different populations studied limited extrapolation of results into recommendations for practice. In some studies, patients taking metformin had improved transaminase levels and insulin levels and decreased liver inflammation and fibrosis on biopsy specimens.66 Other studies failed to show these histologic improvements.67,68

Although not an insulin sensitizer, exenatide (Byetta; a peptide agonist of the glucagon-like peptide-1 receptor) increases insulin’s effect by stimulating the pancreas to release more insulin. It often causes clinically significant weight loss, which has the potential to increase insulin sensitivity. A trial of exenatide’s safety in diabetic patients showed that, over a period of 3.5 years, insulin sensitivity improved, as did transaminase levels. Patients with abnormal ALT levels at the beginning of the trial had significant reductions in ALT levels, and 41% had normalized ALT levels. Several ongoing trials are evaluating exenatide’s effect on NASH.69

In summary, there is some suggestion from controlled trials that use of insulin-sensitizing drugs can lead to beneficial changes for patients with NAFLD and NASH. However, not all studies support this conclusion. A 2007 Cochrane review of the use of insulin-sensitizing drugs for NAFLD and NASH treatment determined there was insufficient evidence to support or refute the use of any drugs for this purpose, and the review recommended more high-quality trials.70

Hepatoprotective Drugs.

Hepatoprotective drugs are the latest group of drugs undergoing investigation for NASH treatment or prevention. The potential benefit of vitamin E, an antioxidant, has already been discussed, but more study is needed before it can be recommended to patients with NASH.63

Probucol (Lorelco), a lipid-lowering drug with antioxidant properties, has been shown to normalize transaminase levels in NASH and to improve histologic grades of steatohepatitis after 1 year.71 Probucol is available in some foreign countries but was removed from the US market in 1995 because of concerns it lowered high-density lipoprotein levels.

Ursodeoxycholic acid, a naturally occurring bile acid, can improve biochemical markers of NASH and insulin resistance, but sequential liver biopsy studies have not shown histologic remission. Other supplements and drugs being evaluated for hepatoprotective properties include omega-3 fatty acids, statins, pentoxifylline, and betaine (Cystadane).53

Prognosis

Nonalcoholic steatohepatitis is now recognized as a significant risk for cirrhosis and hepatocellular carcinoma.72,73 At least 15% of cryptogenic cirrhosis might be caused by NASH.74 Family physicians could have a major effect on outcomes for overweight patients through earlier recognition and treatment of NAFLD/NASH and vigorous efforts to assist patients in decreasing risk of metabolic syndrome development.

Case 3, cont’d. Kelly and her family want to know about her treatment options. You counsel her that the cornerstone of therapy is to treat modifiable risk factors, specifically type 2 diabetes, obesity, and hyperlipidemia. Pioglitazone is added to her treatment regimen. She is counseled on adopting a healthy diet and lifestyle, including at least 60 min/day of physical activity.

SECTION THREE

New Strategies for Cirrhosis Management

Case 4. Jerry is a 56-year-old man with alcohol-induced cirrhosis who is found to have shifting dullness on percussion of the abdomen. Ultrasound demonstrates ascites. He has no fever or abdominal pain.

Background

In the United States, the 2 most common etiologies of cirrhosis are alcoholic liver disease and hepatitis C,75 but cirrhosis can result from many other liver disorders (Table 10). When the etiology is not determined, the condition is called cryptogenic cirrhosis.

Table 10

Most Common Etiologies of Cirrhosis in the United States^a

Alcoholic liver disease

Chronic hepatitis C virus

Chronic hepatitis B virus, with or without concomitant hepatitis D virus infection

Nonalcoholic steatohepatitis (nonalcoholic fatty liver disease)

Autoimmune hepatitis B virus

Biliary cirrhosis

Drugs and toxins

Inherited diseases

Cystic fibrosis

Alpha₁-antitrypsin deficiency

Hemochromatosis

Wilson disease

Galactosemia

Glycogen storage diseases

Parasitic infections

Chronic heart failure with liver congestion

^aListed in approximate order of frequency.

Adapted from National Digestive Diseases Information Clearinghouse. Cirrhosis. 2008. NIH Publication No. 09-1134. Available at http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/#cause.

Cirrhosis and its complications are the 12th leading cause of death among American adults and the 5th leading cause of death among individuals ages 45 to 54 years.76 Hospitalization costs for disease-related complications are estimated at $18,000 per episode of care, and 10% of admitted patients die.77

Initial Detection

Although cirrhosis is typically considered irreversible in its advanced stages, early intervention targeting the etiology can prevent further hepatic injury. Thus, early and accurate diagnosis is essential.

However, early diagnosis is sometimes difficult because patients can initially have few symptoms or signs. Indeed, in the past, cirrhosis was not recognized until autopsy in approximately one-third of cases.78 Now, although patients still can present with the signs and symptoms of advanced liver disease (Table 11), abnormal findings on routine laboratory testing (Table 12) provide an opportunity for early diagnosis in some patients. For those presenting with advanced symptoms, the findings most suggestive of cirrhosis are encephalopathy (likelihood ratio [LR] = 17.5), jaundice (LR = 14.2), and ascites (LR = 3.9).79

Table 11

Classic Physical Examination Findings in Patients With Cirrhosis

Physical Examination Findings	Comment
Skin
Jaundice	Usually not visually detectable until bilirubin level is greater than 3 mg/dL
Palmar erythema	Probably due to estrogenic-stimulated vasodilation of palms
Spider angiomata	Probably due to deficient hepatic metabolism of estrogenic compounds
Hands
Dupuytren contracture	Alcohol-associated tendon and subcutaneous tissue abnormality that results in thickening and shortening of palmar fascia
Hypertrophic osteoarthropathy	Clubbing of nails; more common in primary biliary cirrhosis
Muehrcke lines	White horizontal lines on the fingernails, probably related to hypoalbuminemia
Terry nails	Two-thirds of nail plate is white and distal one-third is red; probably related to hypoalbuminemia
Trunk
Ascites	Due to portal hypertension and hypoalbuminemia
Caput medusae	Umbilical vein obstruction/congestion from portal hypertension
Gynecomastia	Due to deficient hepatic metabolism of estrogenic compounds
Hepatomegaly	Often with a nodular texture on palpation
Splenomegaly	Splenic congestion due to portal hypertension; most common in nonalcoholic cirrhosis
Other findings
Asterixis	Bilateral, asynchronous flapping motions of outstretched, dorsiflexed hands; seen in encephalopathy
Cachexia	Due to malnutrition
Fetor hepaticus	Malodorous breath and body odor of dimethyl sulfide, due to severe portal-systemic shunting
Testicular atrophy	From alcohol-induced injury or suppression of hypothalamic-pituitary function (seen in hemochromatosis)

Table 12

Laboratory Test Results in Patients With Cirrhosis

Indicators of hepatic inflammation

Elevated aspartate aminotransferase level

Elevated alanine aminotransferase level

Indicators of intrahepatic obstruction

Elevated bilirubin level

Elevated alkaline phosphatase level

Elevated gamma-glutamyl transferase level

Indicators of declining hepatic function

Low albumin level

Elevated international normalized ratio

Indicators of bone marrow dysfunction

Thrombocytopenia (earliest hematological abnormality)

Leukopenia

Anemia

Information from Qamar AA, Grace ND, Groszmann RJ, et al; Portal Hypertension Collaborative Group. Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis. Clin Gastroenterol Hepatol. 2009;7(6):689-695.

Diagnosis Confirmation

Ultrasonography is noninvasive, widely available, inexpensive, and involves no risks to the patient, making it the preferred method for confirming the presence of cirrhosis in most patients. Ultrasound shows a cirrhotic liver to be small and nodular. It also can detect complications of cirrhosis, such as hepatocellular carcinoma (HCC), portal hypertension, splenomegaly, and ascites, and with Doppler techniques can provide information about portal blood flow.80 For most patients, any advantages of computed tomography scan, magnetic resonance imaging study, or radionuclide study over ultrasound are outweighed by the cost and the risk of adverse effects from those techniques.

Liver biopsy has traditionally been the gold-standard test for cirrhosis and might be needed when ultra-sound findings are equivocal. Percutaneous, transjugular, laparoscopic, or radiographically guided fine-needle approaches can be used, but all methods expose the patient to procedural risks, especially if clotting is impaired. The procedure also is dependent on the skill of the operator, as well as the extent of hepatic damage, the size of specimen, and the number of specimens taken.81

Management

The goals of cirrhosis management are to prevent further hepatic damage and prevent and/or lessen complications.

Preventing Further Hepatic Damage

Abstinence from alcohol is essential in patients with cirrhosis and is associated with improved survival rates.82 Hepatotoxic drugs and herbal remedies should be avoided; common offending agents are shown in Table 4.

Examples of specific treatments to prevent further hepatic damage include the drug therapies discussed earlier for patients with hepatitis B and C virus, steroids or immunosuppressive drugs for autoimmune hepatitis, phlebotomy for hemochromatosis, and immunization of nonimmune patients against hepatitis A and B virus.

Managing Complications

The most significant and life-threatening complications of cirrhosis are due to portal hypertension. These include ascites, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, acute variceal hemorrhage, and encephalopathy.

Portal Hypertension

Portal hypertension occurs when portal blood flow through the liver is impeded, and the normally low-pressure portal system develops increasingly high pressures. Portal hypertension can be identified on ultrasound by finding an increased diameter of the portal vein and the presence of collateral veins. A large spleen on ultrasound provides indirect evidence of portal hypertension.83

New research emphasizes that the development of portal hypertension is more complicated than just fibrosis and tissue distortion in the liver. Rather, endothelial dysfunction, with vascular hyperresponsiveness and overproduction of vasoconstrictors, such as endothelin-1 and cyclooxygenase-derived prostaglandins, combined with hyporesponsiveness and impaired production of vasodilators, such as nitric oxide, alter the vascular tone at the endothelial level.84 These findings offer future approaches to therapy.

Indeed, medical therapies are evolving that target this hepatic endothelial dysfunction. Recent experimental data suggest that statins (eg, simvastatin 20 mg/day) decrease intrahepatic vascular resistance and, thus, lower portal venous pressure.85,86 This mechanism differs from that of conventional therapy with nonselective beta blockers. Beta blockers also reduce portal pressure by decreasing portocollateral blood flow.87

Ascites

Ascites develops in 50% to 60% of individuals with cirrhosis over 10 years of observation, and its presence indicates decompensated cirrhosis.88 Patients with cirrhosis and who develop ascites have a 5-year survival rate of less than 50%.89 Current guidelines specify that abdominal paracentesis should be performed on all patients with new-onset ascites.90 These guidelines do not recommend use of fresh frozen plasma or other precautions for paracentesis because the risk of bleeding from this relatively simple procedure is small, especially if performed under ultrasound guidance.

The ascitic fluid should be analyzed for complete blood count, white blood cell count differential, total protein, and serum ascites-albumin gradient. Serum ascites-albumin gradient confirms portal hypertension and is calculated by subtracting the ascitic fluid albumin value from the serum albumin value. A gradient of 1.1 g/dL or more indicates portal hypertension. A gradient of less than 1.1 g/dL suggests that ascites might be caused by something other than cirrhosis with portal hypertension.91

In many cases, ascites can be managed with dietary sodium restriction (less than 2,000 mg/day) in combination with diuretics (spironolactone or loop diuretics). Fluid restriction is not necessary unless serum sodium is less than 120 to 125 mEq/L.90

Patients who do not improve with this therapy are considered to have refractory ascites, which has a poor prognosis and is associated with an increased risk of SBP and hepatorenal syndrome. Refractory ascites due to alcoholic cirrhosis can revert to diuretic-responsive ascites after total abstinence from alcohol.

For most patients with refractory ascites, treatment is challenging. The usual options are serial large-volume paracentesis obtained with albumin supplementation, and transjugular intrahepatic portosystemic stent shunt (TIPS). Studies comparing repeated large-volume paracentesis with TIPS yielded conflicting results. Although some have reported advantages from TIPS, procedural risks and a significant excess of encephalopathy in TIPS cases influenced recent American Association for the Study of Liver Diseases guidelines to recommend TIPS only for patients who are intolerant of repeated large-volume paracenteses.92 Patients whose disease is not responsive to these treatments should be considered for liver transplantation.

Spontaneous Bacterial Peritonitis

Spontaneous bacterial peritonitis occurs when ascitic fluid becomes infected because of transcolonic migration of gram-negative or gram-positive bacteria.93 Symptoms can be subtle, and paracentesis is recommend for patients with ascites who develop any signs, symptoms, or laboratory markers of infection (eg, abdominal pain, fever, mental status changes, renal failure, acidosis, peripheral leukocytosis).90 In this setting, a finding of 250 polymorphonuclear leukocytes/mm³ or more in the ascites indicates SBP and warrants empiric antibiotic therapy.

The first-choice antibiotic is intravenous cefotaxime (2 g every 8 hours) for 5 days. If fever or pain persists after 5 days, repeat the paracentesis. Limited data suggest that oral ofloxacin (400 mg 2 times/day) can be substituted for intravenous cefotaxime when treating patients with uncomplicated SBP with no prior exposure to quinolones.94 Guidelines recommend that patients with SBP who also have hyperbilirubinemia (bilirubin level greater than 4 mg/dL) and an elevated creatinine level should receive albumin (1.5 g/kg of body weight) within 6 hours of detection of SBP and 1.0 g/kg on the third day of treatment.95

Ongoing antibiotic prophylaxis is recommended for patients with a previous SBP because without such treatment, SBP recurs within a year in up to 70% of patients.96 The best evidence supports use of oral norfloxacin (Noroxin) (400 mg/day);97 limited evidence supports trimethoprim-sulfamethoxazole as an alternative.98 Patients with a history of SBP who are hospitalized for gastrointestinal bleeding should receive SBP prophylaxis with intravenous ceftriaxone or norfloxacin 2 times/day for 7 days, followed by the previously discussed long-term norfloxacin prophylaxis.

Hepatorenal Syndrome

Hepatorenal syndrome refers to development of acute renal failure in a patient with advanced hepatic disease. The incidence approaches 40% after 5 years.99

Key clinical features of hepatorenal syndrome include a creatinine level greater than 1.5 mg/dL that is not reduced below that level upon administration of albumin (1 g/kg) and after 2 days without diuretics; absence of treatment with nephrotoxic drugs; no hypotension; and no other apparent cause of renal disease.100 A fractional excretion of sodium of less than 1% in the absence of diuretic therapy supports the diagnosis.

Treatment involves correcting hypovolemia and administering vasoconstrictors as part of initial therapy. Treatment with vasoconstricting vasopressin analogues (eg terlipressin [not available in the United States], octreotide), sometimes combined with an alpha-adrenergic agonist, such as midodrine, is the recommended approach and effective in up to half of patients.100,101 Patients awaiting liver transplantation might require dialysis until transplantation can be obtained.

Acute Variceal Hemorrhage

Acute variceal hemorrhage is a severe complication of cirrhosis. Each episode of acute variceal hemorrhage is associated with a 30% mortality rate and survivors have a 50% to 70% risk of recurrent bleeding within 1 year.102 Current guidelines advocate upper endoscopy to screen for varices in all patients with cirrhosis. If varices are present, recommended interventions depend on the size of the varices and the status of hepatic decompensation (determined by the Child-Pugh category). Table 13 outlines the recommended approach.103,104

Table 13

Approach to Patients With Esophageal Varices Without Bleeding

Size of Varices	Child-Pugh Classification^a	Recommended Approach
None	-	No therapy needed. Surveillance EGD in 3 years
Small	A	Consider beta blockers.^b Surveillance EGD in 2 years if not taking beta blockers
Small	B/C	Beta blocker therapy.^b Surveillance EGD not needed if taking beta blockers
Medium/large	A	Beta blocker therapy.^b Consider endoscopic variceal ligation if patient has contraindications to or is intolerant of or nonadherent to beta blocker therapy
Medium/large	B/C	Either beta blocker therapy^b or endoscopic variceal ligation. Surveillance EGD 1 to 3 months after ligation is complete, then every 6 to 12 months

^aChild-Pugh classification calculator is available online at http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality.

^bBeta blocker therapy typically started at 20 mg 2 times/day of propranolol (considered an off-label use by the FDA) or 40 mg/day of nadolol (considered an off-label use by the FDA). Dose is titrated to the maximum tolerated dose.

EGD = esophagogastroduodenoscopy; FDA = Food and Drug Administration.

Information from Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. Erratum in Hepatology. 2007;46(6):2052.

Current guidelines for acute variceal hemorrhage recommend prompt endoscopic treatment (endoscopic band ligation or sclerotherapy) and vasoactive therapy with somatostatin or vasopressin analogues.103 In the past, TIPS was then performed as a rescue therapy when bleeding could not be controlled. New research suggests the effectiveness of TIPS within 72 hours of admission for patients with acute variceal hemorrhage in Child-Pugh class C, regardless of whether bleeding has stopped, or in class B when they have continued bleeding. This drops the 1-year bleeding rate to as low as 3% (compared with 50% with rescue TIPS).105 Thus, early TIPS should be routinely considered in patients with acute variceal bleeding.

Hepatic Encephalopathy

Hepatic encephalopathy occurs in patients with advanced liver decompensation, often precipitated by sedative drugs, electrolyte disturbances, gastrointestinal bleeding, constipation, or infection (including SBP).

Encephalopathy can present with a variety of neuropsychiatric symptoms and physical findings. Sleep disorders are common early symptoms. Later symptoms include confusion, lethargy, and coma. Physical findings include generalized signs of neurologic irritability, such as asterixis, bradykinesia, or decreased tendon reflexes.106 These symptoms and signs are attributed to high levels of arterial ammonia and other nitrogenous toxins bypassing the impaired portal system and acting as neurotoxins.

Prevention and treatment involves removing any precipitating etiologies plus decreasing ammonia absorption from the colon by administering cathartics to remove colonic substrates for nitrogen production by gut flora, or reducing the concentration of those gut flora with nonabsorbable oral antibiotics, such as neomycin and rifaximin (Xifaxan).

Lactulose is the most commonly recommended cathartic. Among the antibiotics, neomycin was used in the past, but now rifaximin often is used. Recent evidence shows that rifaximin, used in combination with lactulose, reduces by half the number of episodes and hospitalizations for encephalopathy.107

Liver Transplantation

Liver transplantation is the definitive therapy for hepatic failure, but it is a complex and expensive procedure with limited availability. Survival rates depend on patient selection and are currently reported to be 88% at 1 year and 73% at 5 years.108

Patients are considered candidates for transplantation based on severity of hepatic dysfunction, absence of alternative treatments, and patient factors influencing good outcomes (ie, lack of comorbidities and substance abuse, ability to adhere to medical and lifestyle recommendations).109

The modified model for end-stage liver disease (MELD) score110 is the most widely accepted measure of eligibility for liver transplantation. The MELD score predicts 3-month survival without transplantation. Scores range from 6 to 40 and patients should have a MELD score of at least 15 to be considered for transplantation.111 A MELD score calculator (United Network for Organ Sharing [UNOS] Modification) can be found on the Medical University of South Carolina’s Web site (http://appserve.musc.edu/pss/calcs/meld1unos.html).

Patients who meet the criteria for transplantation should be referred as early as possible to a center that performs at least 20 transplantations/year. Failure to refer patients in a timely fashion or not recording MELD score in the medical record has been a basis for malpractice litigation.112

Case 4, cont’d. Jerry has new-onset ascites. After initial analysis of the ascites determined that it was from cirrhosis and baseline esophagogastroduodenoscopy detected esophageal varices, Jerry was treated with spironolactone, and strategies to reduce alcohol consumption and hepatic risk factors also were initiated. He successfully discontinued alcohol consumption and has been assessed by and is being monitored by a liver transplantation team. He remains adherent to therapy and follow-up.

SECTION FOUR

Biliary Stone Disease Diagnosis and Management

Cholelithiasis

Cholelithiasis (also known as cholecystolithiasis) is defined as stones in the gallbladder. The condition affects approximately 20 million individuals in the United States (10% to 15% of adults) and approximately 1 million new diagnoses are made annually. By age 60 years, 30% of women and approximately 20% of men have gallstones. By age 80 years, 60% of men and women have detectable gallstones. In at least 80% of these individuals, asymptomatic stones are discovered incidentally.113

Longitudinal studies of patients with asymptomatic gallstones estimate the annual risk of developing symptoms at 1% to 4%. These studies have followed patients for 9 to 20 years and found that only approximately 20% of patients with asymptomatic gallstones ever develop biliary pain, most within 5 years after identification of the gallstones.114,115 Symptoms are more likely to develop in patients older than 70 years. Higher rates of complications have been associated with larger (less than 2.5 cm) stones, multiple stones, or stones occluding the cystic duct.115

Case 5. Anita is a 40-year-old woman who presents with a 1-hour history of upper abdominal pain with nausea and vomiting. The pain began soon after she consumed a large meal. A similar episode 2 weeks ago resolved spontaneously. She is starting to feel better and has no fever.

Presentation

Most patients who experience pain from gallstones have mild, recurrent episodes of abdominal pain. Only an estimated 20% of those who become symptomatic develop severe pain or complications such as acute cholecystitis, and less than 10% progresses to complications, such as cholangitis or pancreatitis. Cholecystitis and other complications rarely develop without previous episodes of biliary pain.115

The cardinal symptom of gallstones is a moderately severe, crescendo-type pain in the right upper quadrant (RUQ) radiating to the back and/or right shoulder. In classic cases, the pain can start after a fatty meal and progress in less than an hour to a plateau of moderate to severe pain, but episodes of pain also can be unrelated to meals. Pain typically remains constant for more than an hour, and then subsides over several hours. An episode of prolonged RUQ pain (greater than 4 to 6 hours), especially if associated with fever, should arouse suspicion of acute cholecystitis.

Patients often experience several such episodes before seeking medical attention. The frequency of recurrence ranges from hours to years. Biliary pain is not positional and is not relieved by bowel movements or flatus. Dyspepsia frequently occurs.

Physical Examination

Patients with simple biliary colic typically do not appear ill or distressed and do not have fever or tachycardia. Even during a pain episode, abdominal examination findings are typically benign, although tenderness upon deep palpation or voluntary guarding might be detectable in the right upper abdomen.

Right upper quadrant tenderness is neither highly specific nor highly sensitive for detecting gallstones. No peritoneal signs are detectable because the pain is visceral (caused by a stone obstructing the gallbladder outlet) rather than because of inflammation. Murphy sign is negative.

Laboratory Tests

Even during symptomatic episodes, laboratory study results should be normal in patients with uncomplicated cholelithiasis. The principal role of laboratory testing is to exclude other diagnoses by obtaining studies to assess the liver (aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, and gamma-glutamyl transferase) and pancreas (serum amylase and lipase), and a complete blood count for leukocytosis and anemia. Urinalysis might also be warranted to differentiate urolithiasis from biliary sources of symptoms.

Imaging Studies

Ultrasound is the most useful test for confirming the presence of gallstones or sludge in a symptomatic patient. Ultrasound has a reported 84% sensitivity and 99% specificity for detecting cholelithiasis.116

Management

Asymptomatic Gallstones.

There is less than a 4% annual risk that asymptomatic gallstones will become symptomatic. As a result, both past and current practice guidelines state that surgery is not indicated for treating asymptomatic gallstones because the risk of surgery outweighs the risk of gallstone complications for the majority of patients.117,118 A Cochrane review identified no randomized trials of surgery versus no surgery for asymptomatic stones.119 Elective cholecystectomy is sometimes recommended for patients at high risk of developing symptoms or complications (eg, chronic hemolytic conditions) or if abdominal surgery is performed for another condition.115

Symptomatic Stones.

Symptomatic stones have a higher rate of recurrence. After experiencing symptoms once, up to half of patients will experience recurrent symptoms, and a 1% to 2% chance of biliary complications.118 Therefore, if symptoms are recurrent or severe, surgery is indicated.

Surgery.

In the past, open cholecystectomy was the procedure most often used to treat gallstones. However, with the advent of laparoscopic procedures, laparoscopic cholecystectomy rapidly became the procedure of choice for most patients, bypassing other procedures that were in development at that time, notably small-incision cholecystectomy (mini-laparotomy).

More recently, there has been resurgent interest in—and increased availability of—small-incision cholecystectomy. A 2010 Cochrane review evaluated 56 studies comparing classic open, laparoscopic, and small-incision cholecystectomy (Table 14) and raised questions about why laparoscopic procedures have become dominant. The review showed that small-incision and laparoscopic cholecystectomy have much shorter recovery times but higher complication rates than classic open cholecystectomy, the latter likely because of differences in operator experience. But, if the choice is between a small-incision and laparoscopic procedure, evidence favors small-incision cholecystectomy. Both have approximately the same complication rate, but the cost is lower and the operative time is shorter with small-incision procedures.120

Table 14

Comparisons of Open, Laparoscopic, and Small-Incision Cholecystectomy

Outcomes	Open	Laparoscopic	Small-Incision
Total complications	9.3% to 10.1%	5.4% to 26.6%	9.9% to 22.9%
Severe complications	2.5% to 6.8%	2.2% to 4.0%	1.4% to 4.2%
Mortality	<0.1%	<0.1%	<0.1%
Need to convert to open procedure	-	13.4%	16.1%
Mean length of stay (compared to open procedure)	-	3.07 days shorter	2.78 days shorter
Mean length of time for return to work (compared to open procedure)	-	22.5 days sooner	22.9 days sooner

Information from Keus F, Gooszen HG, van Laarhoven CJ. Open, small-incision, or laparoscopic cholecystectomy for patients with symptomatic cholecystolithiasis. An overview of Cochrane Hepato-Biliary Group reviews. Cochrane Database Syst Rev. 2010;(1):CD008318.

Medical Management of Acute Biliary Pain Episodes.

Medical management of acute biliary pain episodes for patients who have not yet undergone cholecystectomy involves analgesia and symptom control. Intramuscular ketorolac is the first-line drug because it provides good pain relief, has fewer adverse effects than narcotics, and does not cause the delay in gallbladder emptying (due to contraction of the sphincter of Oddi) that can occur with narcotic analgesics.121

Treatment of Patients Not Undergoing Surgery.

Treatment often involves bile acid therapy (ursode-oxycholic oxycholic acid) to dissolve stones. This is an appropriate therapy for patients who are not candidates for surgery, and for those with mild symptoms. Approximately 50% of patients treated with bile acid therapy experience symptomatic stone recurrence within 5 years after discontinuation of this treatment. In patients with stones too large for dissolution therapy, lithotripsy (plus bile acid therapy) can be considered.

Case 5, cont’d. Anita received intramuscular ketorolac and her pain resolved promptly. The next day an ultrasound confirmed the presence of gallstones without biliary duct dilatation. She was referred for elective small-incision cholecystectomy.

Acute Cholecystitis

Acute cholecystitis accounts for 3% to 9% of US hospitalizations for acute abdominal pain.122 It is defined as a syndrome of abdominal pain, fever, and leukocytosis associated with gallbladder inflammation, typically because of gallstones.123

Case 6. Yvette is a 55-year-old woman who presents to the emergency department with postprandial right upper quadrant (RUQ) pain and vomiting for 6 hours. The pain is persistent and radiates to her back and right shoulder. She is febrile. The abdomen is tender to RUQ palpation and Murphy sign is positive. Ultrasound shows cholelithiasis and gallbladder wall edema. The white blood cell count and alkaline phosphatase level are elevated, but bilirubin and transaminase levels are normal.

Presentation

Patients typically present with steady, severe RUQ or epigastric pain that can radiate to the right shoulder or back, and often is associated with nausea, vomiting, and anorexia. However, a wide range of symptom severity is possible. Elderly patients might present with atypical pain and progress more rapidly to severe cholecystitis.124

The clinical diagnosis is based on the overall presentation, and the strongest indicators of cholecystitis

are RUQ pain and/or tenderness, positive Murphy sign, and nausea. Laboratory test results can reveal leukocytosis and elevated alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and bilirubin levels.116,124

Imaging Studies

Ultrasonography has a sensitivity of 88% to 94% and specificity of 78% to 80% for identifying acute cholecystitis and is the preferred initial test.116 Indications of cholecystitis found by ultrasound are thickening or edema of the gallbladder wall and a sonographic Murphy sign (tenderness over the gallbladder elicited by the transducer, producing inspiratory arrest). Gallstones often are present.

Nuclear cholescintigraphy, known as a hepatoiminodiacetic acid (HIDA) scan, is useful when the diagnosis remains uncertain after ultrasonography. A positive HIDA scan result means that radiotracer-labeled bile does not fill the gallbladder, resulting in nonvisualization, probably because of a swollen or obstructed cystic duct. Computed tomography scan is inferior to ultrasound and HIDA scans in diagnosing cholecystitis, but might identify other conditions in the differential diagnosis.

Treatment

Although acute cholecystitis can abate within 7 to 10 days without treatment, the probability of serious complications mandates intervention. The most serious common complication is gangrene of the gallbladder (up to 40% of untreated cases in some series) with subsequent perforation in a small percentage of cases.125

Patients with acute cholecystitis should be hospitalized. They should receive intravenous hydration and undergo nasogastric suctioning if they experience persistent vomiting.

Antibiotics.

Antibiotics often are administered to patients with acute cholecystitis, but the condition is an inflammatory process and infection might or might not be present. Current guidelines from the Infectious Diseases Society of America state that antimicrobial therapy should be provided if infection is suspected on the basis of clinical findings. The guideline suggests antibiotics, including ampicillin-sulbactam, piperacillin-tazobactam, ticarcillin-clavulanic acid (Timentin), or the combination of a third-generation cephalosporin and metronidazole.126 Antibiotics also are recommended in vulnerable patients, such as elderly patients, diabetes patients, or immunocompromised patients, and prophylactically for those undergoing cholecystectomy.127

Analgesia.

Analgesia with nonsteroidal anti-inflammatory drugs has been shown to be as effective as narcotics in relieving pain and can prevent narcotic-induced spasm of the sphincter of Oddi in patients with gallstones. Patients who continue to experience severe symptoms despite medical treatment could require gallbladder drainage by percutaneous cholecystostomy.

Cholecystectomy.

Cholecystectomy is recommended after an episode of acute cholecystitis, but the optimal timing of cholecystectomy has been uncertain. Some surgeons advocate early operation, whereas others favor surgery after resolution of the acute episode. A Cochrane review and several meta-analyses of laparoscopic cholecystectomy128,129,130 have indicated that both strategies have comparable safety and rates of conversion to open procedures, but early cholecystectomy (within 72 hours of diagnosis) is more effective for preventing complications and reducing the length of hospital stays.

Case 6, cont’d. Yvette is hospitalized for intravenous hydration and nasogastric suctioning. Because she is febrile with leukocytosis, antibiotics are initiated. The fever defervesces within the first 24 hours, and laboratory test results start to improve. The surgeon performs a cholecystectomy on the third hospital day, and Yvette makes a full recovery.

Choledocholithiasis

Choledocholithiasis, or common bile duct stones (CBDS), are gallstones that typically originate in the gallbladder and migrate to the common bile duct. Why stones migrate into the ducts remains unclear. In some patients, especially those of Asian descent, stones can form within the biliary ducts themselves. It also is unclear why some stones (approximately 30%) pass into the duodenum without causing symptoms, whereas others cause serious complications.131

Case 7. Marion is a 65-year-old woman who presents to the emergency department with postprandial right upper quadrant (RUQ) pain, nausea, and emesis for 12 hours. The pain is persistent and radiates to her back. She is afebrile and has RUQ tenderness. Ultrasound shows cholelithiasis, gallbladder wall thickening, and a dilated common bile duct. Laboratory test results reveal elevated white blood cell count, transaminase, alkaline phosphatase, gamma-glutamyl transferase, and direct bilirubin levels.

Presentation

Signs and symptoms of CBDS include biliary colic lasting hours, RUQ pain and tenderness, and nausea and vomiting. If the duct is significantly obstructed, patients will have jaundice, pale stools, and dark urine. Laboratory test results typically show a pattern similar to those of the patient in Case 7.

Imaging Studies

Abdominal ultrasound can suggest the diagnosis, particularly if the ducts are dilated. But a negative ultrasound result does not rule out CBDS. Therefore, when the diagnosis is uncertain after abdominal ultrasound, consider additional studies to confirm the diagnosis.

Confirmation can be obtained using endoscopic ultrasound, magnetic resonance cholangiopancreatography, or endoscopic cholangiopancreatography (ERCP). All have similar sensitivity (80% to 100%) and specificity (90% to 100%), and all perform better than computed tomography scan for identifying CBDS in most situations.132,133 Thus, a decision on which approach to use must be individualized based on patient needs. For example, magnetic resonance cholangiopancreatography cannot be used for patients with metallic implants, and it often is a poor choice for patients who find it difficult to be in a magnetic resonance imaging scanner because of claustrophobia or morbid obesity. ERCP carries the risk of instrumentation and the possibility of inducing pancreatitis, but offers the advantage of immediate stone removal. Finally, specific tests might not be locally available and results often are dependent on the expertise of technicians or those interpreting the images. In the situation in which none of these tests is unavailable, it usually is necessary to transport the patient to a medical center where such tests are available, with the urgency of transport determined by the patient’s medical condition.

Treatment

In almost all cases, symptomatic CBDS should be removed to prevent complications. Stones can be removed via ERCP or bile duct exploration at the time of cholecystectomy. A Cochrane review found that these methods have similar success rates, and similar mortality rates (1% to 5%) and complication rates (2% to 17%). ERCP requires a shorter hospital stay but also often requires repeat procedures.134 Stones that are difficult to remove also can be managed via endoscopic biliary stenting plus mechanical or extracorporeal shock-wave lithotripsy. The choice of procedure might depend on available expertise and patient/family decisions.

Case 7, cont’d. Marion is admitted to the hospital and undergoes endoscopic cholangiopancreatography with sphincterotomy and common bile duct stone extraction. She makes a full recovery.

Cholangitis

Acute cholangitis results from partial or complete obstruction of the biliary system from any etiology. Clinically, the presentation can range from localized biliary infection to sepsis with multiorgan failure.135

Diagnosis

According to current guidelines, the presence of fever, abdominal pain, and jaundice (Charcot triad) is sufficient to make the diagnosis. In the absence of Charcot triad, the diagnosis is made if the patient has a constellation of findings, including elevated white blood cell count or C-reactive protein, abnormal liver test results, biliary dilation or a structural bile duct abnormality, and at least 2 of the following: history of biliary disease, fever/chills, jaundice, and abdominal pain.135

Treatment

Treatment involves gastrointestinal rest, intravenous fluids, and broad-spectrum antibiotics. The Infectious Diseases Society of America recommends the same antibiotics listed in its guideline for treatment of acute cholecystitis, though some experts add a fluoroquinolone because this class of antibiotics has high rates of biliary excretion.136 Cholangitis improves with this treatment a majority of the time.

For those who do not improve over 24 hours or who have signs of septic shock, urgent biliary decompression is required. For most patients, endoscopic sphincterotomy with stone extraction and/or stent insertion is now the treatment of choice for establishing biliary decompression. CBDS causing cholangitis can be removed successfully by this procedure in 90% to 95% of patients.131

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Hepatobiliary Conditions

Learning Objectives

Key Practice Recommendations

Author Information

New Strategies in the Diagnosis and Management of Chronic Viral Hepatitis

Hepatitis C Virus

Hepatitis B Virus

Nonalcoholic Fatty Liver Disease and Steatohepatitis

Background

Etiologies

Diagnosis

Treatment

Prognosis

New Strategies for Cirrhosis Management

Background

Initial Detection

Diagnosis Confirmation

Management

Managing Complications

Biliary Stone Disease Diagnosis and Management

Cholelithiasis

Acute Cholecystitis

Choledocholithiasis

Cholangitis

References

Suggested Reading