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Disorders of the Liver PTEN hamartoma syndrome is caused by germline muta- Elevations in alkaline phosphatase (ALP) and bilirubin tions in the tumor suppressor gene PTEN. Macrocephaly and levels represent a cholestatic pattern and typically result from characteristic benign skin findings are common, including biliary tree abnormalities. ALP is also produced in bone, red facial trichilemmomas, lipomas, and oral papillomas. blood cells, and placenta, and high levels occur in pregnancy. ALP fractionation can determine the source of elevation. Serrated Polyposis Syndrome Bilirubin has unconjugated and conjugated forms.

PTEN hamartoma syndrome is caused by germline muta- Elevations in alkaline phosphatase (ALP) and bilirubin tions in the tumor suppressor gene PTEN. Macrocephaly and levels represent a cholestatic pattern and typically result from characteristic benign skin findings are common, including biliary tree abnormalities. ALP is also produced in bone, red facial trichilemmomas, lipomas, and oral papillomas. blood cells, and placenta, and high levels occur in pregnancy. ALP fractionation can determine the source of elevation. Serrated Polyposis Syndrome Bilirubin has unconjugated and conjugated forms. Serrated polyposis syndrome is characterized by numerous Unconjugated hyperbilirubinemia often results from increased serrated polyps in the colon and an increased risk for colon heme turnover in hematologic disease or benign alterations of cancer. The definition is based on having either of the follow- bilirubin conjugation, such as Gilbert syndrome. Conjugated ing over the patient’s lifetime: hyperbilirubinemia usually reflects a liver disorder. Prothrombin time and serum albumin levels may reflect e Five or more serrated polyps proximal to the rectum, all at liver synthetic function, but other causes of abnormalities are least 5 mm and with two or more at least 10 mm also common. Albumin levels can be decreased in malnutrition, e More than 20 serrated polyps throughout the colon, at the nephrotic syndrome, acute inflammation, and protein- least five located proximal to the rectum losing enteropathies. Prothrombin time can be prolonged in Estimates suggest that the prevalence of serrated polypo- vitamin K deficiency, warfarin therapy, inherited or acquired sis syndrome is 0.3% to 0.6%. The genetic basis of the syn- factor deficiency, and the antiphospholipid antibody syn- drome is unknown, although smoking appears to be a risk drome. The relative levels and severity of AST, ALT, and ALP factor. Colonoscopy is recommended every 1 to 3 years with elevations provide clues about the cause of liver disease removal of all polyps greater than 5 mm. Surgery may be con- (Table 29). The duration of abnormal liver test results is also sidered if the polyps cannot be managed endoscopically. No important in evaluating causes of liver injury (acute liver inflam- extracolonic manifestations have been noted in serrated poly- mation: <6 months’ duration; chronic hepatitis: >6 months’ posis syndrome. duration). Abdominal imaging can be helpful in evaluating abnor- mal liver test results. Abdominal ultrasonography is an appro- e Lynch syndrome is caused by germline mutations in the priate initial modality and may show increased echogenicity, mismatch repair genes and carries a lifetime risk for consistent with fatty infiltration of the liver, as well as liver colorectal cancer of 50% to 80%. nodularity in patients with cirrhosis. Cross-sectional imaging, e Lynch syndrome should be suspected in patients with syn- including CT and MRI, may show fatty infiltration of the liver, chronous or metachronous colorectal cancers, colorectal changes of cirrhosis, or sequelae of portal hypertension. cancer before 50 years of age, occurrence of multiple When fibrosis and cirrhosis are suspected, both serologic Lynch syndrome-associated cancers, or family history of and imaging techniques are increasingly used to detect and multiple cancers associated with Lynch syndrome. estimate the extent of fibrosis and potentially avoid biopsy. The ¢ Colectomy is the treatment of choice for classic familial AST-to-platelet ratio and several proprietary serologic tests adenomatous polyposis and may be pursued in patients may provide valuable information on the degree of underlying with the attenuated form of the disease. fibrosis. Elastography is a noninvasive imaging technique (including ultrasonography, MRI, and transient elastography) that assesses liver stiffness as a measure of fibrosis. High stiff-

Serrated polyposis syndrome is characterized by numerous Unconjugated hyperbilirubinemia often results from increased serrated polyps in the colon and an increased risk for colon heme turnover in hematologic disease or benign alterations of cancer. The definition is based on having either of the follow- bilirubin conjugation, such as Gilbert syndrome. Conjugated ing over the patient’s lifetime: hyperbilirubinemia usually reflects a liver disorder. Prothrombin time and serum albumin levels may reflect e Five or more serrated polyps proximal to the rectum, all at liver synthetic function, but other causes of abnormalities are least 5 mm and with two or more at least 10 mm also common. Albumin levels can be decreased in malnutrition, e More than 20 serrated polyps throughout the colon, at the nephrotic syndrome, acute inflammation, and protein- least five located proximal to the rectum losing enteropathies. Prothrombin time can be prolonged in Estimates suggest that the prevalence of serrated polypo- vitamin K deficiency, warfarin therapy, inherited or acquired sis syndrome is 0.3% to 0.6%. The genetic basis of the syn- factor deficiency, and the antiphospholipid antibody syn- drome is unknown, although smoking appears to be a risk drome. The relative levels and severity of AST, ALT, and ALP factor. Colonoscopy is recommended every 1 to 3 years with elevations provide clues about the cause of liver disease removal of all polyps greater than 5 mm. Surgery may be con- (Table 29). The duration of abnormal liver test results is also sidered if the polyps cannot be managed endoscopically. No important in evaluating causes of liver injury (acute liver inflam- extracolonic manifestations have been noted in serrated poly- mation: <6 months’ duration; chronic hepatitis: >6 months’ posis syndrome. duration). Abdominal imaging can be helpful in evaluating abnor- mal liver test results. Abdominal ultrasonography is an appro- e Lynch syndrome is caused by germline mutations in the priate initial modality and may show increased echogenicity, mismatch repair genes and carries a lifetime risk for consistent with fatty infiltration of the liver, as well as liver colorectal cancer of 50% to 80%. nodularity in patients with cirrhosis. Cross-sectional imaging, e Lynch syndrome should be suspected in patients with syn- including CT and MRI, may show fatty infiltration of the liver, chronous or metachronous colorectal cancers, colorectal changes of cirrhosis, or sequelae of portal hypertension. cancer before 50 years of age, occurrence of multiple When fibrosis and cirrhosis are suspected, both serologic Lynch syndrome-associated cancers, or family history of and imaging techniques are increasingly used to detect and multiple cancers associated with Lynch syndrome. estimate the extent of fibrosis and potentially avoid biopsy. The ¢ Colectomy is the treatment of choice for classic familial AST-to-platelet ratio and several proprietary serologic tests adenomatous polyposis and may be pursued in patients may provide valuable information on the degree of underlying with the attenuated form of the disease. fibrosis. Elastography is a noninvasive imaging technique (including ultrasonography, MRI, and transient elastography) that assesses liver stiffness as a measure of fibrosis. High stiff- Disorders of the Liver ness values may also occur with hepatic congestion, infiltrative disorders, and bile duct obstruction.

Serrated polyposis syndrome is characterized by numerous Unconjugated hyperbilirubinemia often results from increased serrated polyps in the colon and an increased risk for colon heme turnover in hematologic disease or benign alterations of cancer. The definition is based on having either of the follow- bilirubin conjugation, such as Gilbert syndrome. Conjugated ing over the patient’s lifetime: hyperbilirubinemia usually reflects a liver disorder. Prothrombin time and serum albumin levels may reflect e Five or more serrated polyps proximal to the rectum, all at liver synthetic function, but other causes of abnormalities are least 5 mm and with two or more at least 10 mm also common. Albumin levels can be decreased in malnutrition, e More than 20 serrated polyps throughout the colon, at the nephrotic syndrome, acute inflammation, and protein- least five located proximal to the rectum losing enteropathies. Prothrombin time can be prolonged in Estimates suggest that the prevalence of serrated polypo- vitamin K deficiency, warfarin therapy, inherited or acquired sis syndrome is 0.3% to 0.6%. The genetic basis of the syn- factor deficiency, and the antiphospholipid antibody syn- drome is unknown, although smoking appears to be a risk drome. The relative levels and severity of AST, ALT, and ALP factor. Colonoscopy is recommended every 1 to 3 years with elevations provide clues about the cause of liver disease removal of all polyps greater than 5 mm. Surgery may be con- (Table 29). The duration of abnormal liver test results is also sidered if the polyps cannot be managed endoscopically. No important in evaluating causes of liver injury (acute liver inflam- extracolonic manifestations have been noted in serrated poly- mation: <6 months’ duration; chronic hepatitis: >6 months’ posis syndrome. duration). Abdominal imaging can be helpful in evaluating abnor- mal liver test results. Abdominal ultrasonography is an appro- e Lynch syndrome is caused by germline mutations in the priate initial modality and may show increased echogenicity, mismatch repair genes and carries a lifetime risk for consistent with fatty infiltration of the liver, as well as liver colorectal cancer of 50% to 80%. nodularity in patients with cirrhosis. Cross-sectional imaging, e Lynch syndrome should be suspected in patients with syn- including CT and MRI, may show fatty infiltration of the liver, chronous or metachronous colorectal cancers, colorectal changes of cirrhosis, or sequelae of portal hypertension. cancer before 50 years of age, occurrence of multiple When fibrosis and cirrhosis are suspected, both serologic Lynch syndrome-associated cancers, or family history of and imaging techniques are increasingly used to detect and multiple cancers associated with Lynch syndrome. estimate the extent of fibrosis and potentially avoid biopsy. The ¢ Colectomy is the treatment of choice for classic familial AST-to-platelet ratio and several proprietary serologic tests adenomatous polyposis and may be pursued in patients may provide valuable information on the degree of underlying with the attenuated form of the disease. fibrosis. Elastography is a noninvasive imaging technique (including ultrasonography, MRI, and transient elastography) that assesses liver stiffness as a measure of fibrosis. High stiff- Disorders of the Liver ness values may also occur with hepatic congestion, infiltrative disorders, and bile duct obstruction. Approach to the Patient With Abnormal Liver Chemistry Studies e Elevated aspartate aminotransferase and alanine ami-

Disorders of the Liver ness values may also occur with hepatic congestion, infiltrative disorders, and bile duct obstruction. Approach to the Patient With Abnormal Liver Chemistry Studies e Elevated aspartate aminotransferase and alanine ami- Results of liver chemistry tests are frequently abnormal, and it notransferase levels represent hepatic parenchymal is important to take a systematic approach to their evaluation. inflammation; alanine aminotransferase levels are more In general, liver test abnormalities can be used to categorize specific for hepatic inflammation. liver disease into hepatocellular or cholestatic patterns. e Elevations in alkaline phosphatase and bilirubin levels Elevations of aspartate aminotransferase (AST) and ala- represent a cholestatic pattern and may result from bil- nine aminotransferase (ALT) levels represent a hepatocellular iary abnormalities. pattern, reflecting hepatic parenchymal inflammation (hepa- ¢ Prothrombin time and serum albumin levels reflect liver titis). Elevated ALT levels are more specific for hepatic inflam- synthetic function. mation because AST is also found in other tissues, such as e Elastography is a noninvasive imaging technique that HVC heart and muscle. In patients with elevated aminotransferase assesses liver stiffness as a measure of fibrosis and may levels, an AST-to-ALT ratio greater than 1 can suggest advanced avoid biopsy. liver disease as a result of decreased hepatic synthesis of ALT. 52

Disorders of the Liver TABLE 29. Typical Liver Chemistry Studies in Common Hepatobiliary Disorders | Disease AST ALT Bilirubin Other Features Acute viral hepatitis tial TTT NormaltoT — Normalto TTT Exposure history, fatigue, nausea | Chronic viral hepatitis fi TT Normal to T Normal History of exposure to infected | blood or body fluids Nonalcoholic steatohepatitis Normal to T Normal to T Normal to T Normal Metabolic syndrome Alcoholic hepatitis TT Normal to T Normal to TTT Excess alcohol intake | Acute autoimmune hepatitis elt TTT NormaltoT — Normalto TT Autoantibodies Chronic autoimmune tT TT Normal to T Normal Autoantibodies | hepatitis Wilson disease i q T and often Hemolysis if acute, neurologic | unconjugated symptoms if chronic | | a,-Antitrypsin deficiency T T Normal Normal May have pulmonary disease Hemochromatosis Normal Normal Normal Normal Joint symptoms, family history, other organ involvement

| a,-Antitrypsin deficiency T T Normal Normal May have pulmonary disease Hemochromatosis Normal Normal Normal Normal Joint symptoms, family history, other organ involvement Primary biliary cholangitis T tT Normal Female, sicca symptoms, antimitochondrial antibody Primary sclerosing cholangitis 7 tT Normal Ulcerative colitis, abnormal cholangiogram Large-duct obstruction T (97 if T (TT if TT Pain if acute, dilated ducts on acute) acute) imaging Infiltrative liver disease f it Normal Features of malignancy, sarcoid, amyloid, or infection (fungal or mycobacterial) i | | Hepatic ischemia TMT TTT Normal Normal AST >5000 U/L, history of hypotension

Infiltrative liver disease f it Normal Features of malignancy, sarcoid, amyloid, or infection (fungal or mycobacterial) i | | Hepatic ischemia TMT TTT Normal Normal AST >5000 U/L, history of hypotension Celiac disease Normal to T Normal to T Normal to T Normal Usually other features of celiac disease Congestive hepatopathy Normal to T Normal to T Normal to T T to TTT Cardiac disease, elevated jugular venous pressure ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Congestive hepatopathy Normal to T Normal to T Normal to T T to TTT Cardiac disease, elevated jugular venous pressure ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase. Viral Hepatitis studies may show aminotransferase levels exceeding 1000 U/L and total bilirubin level of 10 mg/dL (171 pmol/L) or higher, Hepatitis A mostly direct (conjugated). Acute illness is diagnosed by HAV Hepatitis A virus (HAV) is an RNA virus causing acute hepati- IgM antibodies, although false-positive results may occur tis mediated by the host immune response. HAV infection is within the setting of other viral infections. HAV IgG antibodies usually self-limited, but atypical forms include relapsing- indicate previous infection or vaccination and provide immu- remitting infection with cholestatic features and, rarely, acute nity from reinfection. Treatment is supportive, and at least 90% liver failure. HAV transmission is fecal-oral. Risk factors of patients recover fully within 3 to 6 months of infection. include international travel, contacts with HAV-infected HAV can be transmitted during the prodrome stage and household members, men who have sex with men, homeless- up to 1 week after development of jaundice. Persons who have ness, and exposure to day care or institutionalized settings. recently been exposed to HAV and have not been immunized HAV incidence declined dramatically after introduction of should receive postexposure prophylaxis as soon as possible universal childhood HAV vaccination, but rates have recently increased among unvaccinated people, especially those (within 2 weeks of exposure). Postexposure prophylaxis

Viral Hepatitis studies may show aminotransferase levels exceeding 1000 U/L and total bilirubin level of 10 mg/dL (171 pmol/L) or higher, Hepatitis A mostly direct (conjugated). Acute illness is diagnosed by HAV Hepatitis A virus (HAV) is an RNA virus causing acute hepati- IgM antibodies, although false-positive results may occur tis mediated by the host immune response. HAV infection is within the setting of other viral infections. HAV IgG antibodies usually self-limited, but atypical forms include relapsing- indicate previous infection or vaccination and provide immu- remitting infection with cholestatic features and, rarely, acute nity from reinfection. Treatment is supportive, and at least 90% liver failure. HAV transmission is fecal-oral. Risk factors of patients recover fully within 3 to 6 months of infection. include international travel, contacts with HAV-infected HAV can be transmitted during the prodrome stage and household members, men who have sex with men, homeless- up to 1 week after development of jaundice. Persons who have ness, and exposure to day care or institutionalized settings. recently been exposed to HAV and have not been immunized HAV incidence declined dramatically after introduction of should receive postexposure prophylaxis as soon as possible universal childhood HAV vaccination, but rates have recently increased among unvaccinated people, especially those (within 2 weeks of exposure). Postexposure prophylaxis reporting homelessness or drug use (see MKSAP 19 General should consist of HAV vaccine in all nonimmune persons age

Viral Hepatitis studies may show aminotransferase levels exceeding 1000 U/L and total bilirubin level of 10 mg/dL (171 pmol/L) or higher, Hepatitis A mostly direct (conjugated). Acute illness is diagnosed by HAV Hepatitis A virus (HAV) is an RNA virus causing acute hepati- IgM antibodies, although false-positive results may occur tis mediated by the host immune response. HAV infection is within the setting of other viral infections. HAV IgG antibodies usually self-limited, but atypical forms include relapsing- indicate previous infection or vaccination and provide immu- remitting infection with cholestatic features and, rarely, acute nity from reinfection. Treatment is supportive, and at least 90% liver failure. HAV transmission is fecal-oral. Risk factors of patients recover fully within 3 to 6 months of infection. include international travel, contacts with HAV-infected HAV can be transmitted during the prodrome stage and household members, men who have sex with men, homeless- up to 1 week after development of jaundice. Persons who have ness, and exposure to day care or institutionalized settings. recently been exposed to HAV and have not been immunized HAV incidence declined dramatically after introduction of should receive postexposure prophylaxis as soon as possible universal childhood HAV vaccination, but rates have recently increased among unvaccinated people, especially those (within 2 weeks of exposure). Postexposure prophylaxis reporting homelessness or drug use (see MKSAP 19 General should consist of HAV vaccine in all nonimmune persons age Internal Medicine 2). 12 months or older. Immunoglobulin administration may be

Viral Hepatitis studies may show aminotransferase levels exceeding 1000 U/L and total bilirubin level of 10 mg/dL (171 pmol/L) or higher, Hepatitis A mostly direct (conjugated). Acute illness is diagnosed by HAV Hepatitis A virus (HAV) is an RNA virus causing acute hepati- IgM antibodies, although false-positive results may occur tis mediated by the host immune response. HAV infection is within the setting of other viral infections. HAV IgG antibodies usually self-limited, but atypical forms include relapsing- indicate previous infection or vaccination and provide immu- remitting infection with cholestatic features and, rarely, acute nity from reinfection. Treatment is supportive, and at least 90% liver failure. HAV transmission is fecal-oral. Risk factors of patients recover fully within 3 to 6 months of infection. include international travel, contacts with HAV-infected HAV can be transmitted during the prodrome stage and household members, men who have sex with men, homeless- up to 1 week after development of jaundice. Persons who have ness, and exposure to day care or institutionalized settings. recently been exposed to HAV and have not been immunized HAV incidence declined dramatically after introduction of should receive postexposure prophylaxis as soon as possible universal childhood HAV vaccination, but rates have recently increased among unvaccinated people, especially those (within 2 weeks of exposure). Postexposure prophylaxis reporting homelessness or drug use (see MKSAP 19 General should consist of HAV vaccine in all nonimmune persons age Internal Medicine 2). 12 months or older. Immunoglobulin administration may be Mortality is rare but may be increased in patients with considered in addition to vaccination in patients older than

reporting homelessness or drug use (see MKSAP 19 General should consist of HAV vaccine in all nonimmune persons age Internal Medicine 2). 12 months or older. Immunoglobulin administration may be Mortality is rare but may be increased in patients with considered in addition to vaccination in patients older than preexisting chronic liver disease. The incubation period for age 40 years because vaccine efficacy is uncertain in older HAV is 15 to 50 days. A prodrome of malaise, nausea, vomiting, patients. Immunoglobulin may also be administered to per- fever, and right-upper-quadrant pain is followed approxi- sons at high risk for complications, including those with mately 1 week later by jaundice and hepatomegaly. Laboratory chronic liver disease and immunosuppression. 53

Disorders of the Liver TABLE 30. Indications for Hepatitis B Virus Testing? Individuals born or raised in regions with high rates of hepatitis B virus infection, including Asia, Africa, the South Pacific, European Mediterranean countries, Eastern Europe, most of South America, Honduras, Guatemala, and the Middle East (except Israel and Cyprus) U.S.-born persons not vaccinated as infants whose parents were born in endemic areas Household or sexual contact with hepatitis B surface antigen-positive persons Intravenous drug use Multiple sex partners or history of sexually transmitted infection Men who have sex with men History of incarceration History of hepatitis C virus Persons with HIV infection Persons undergoing predialysis, hemodialysis, peritoneal dialysis, or home dialysis Persons with developmental disabilities and staff in residential facilities for persons with developmental disabilities Pregnancy Before initiation of immunosuppressive or cytotoxic therapy Elevated aminotransferase levels of unknown cause #Recommendations collated from the CDC, U.S. Preventive Services Task Force, and American Association for the Study of Liver Diseases. Hepatitis B immunosuppressive or cytotoxic therapy (Table 30); anti- HBV Hepatitis B virus (HBV) is a DNA virus affecting 240 million prophylactic treatment should be considered in patients with persons worldwide. See MKSAP 19 General Internal Medicine chronic HBV infection. Interpretation of screening test results 2 for HBV vaccination strategies. HBV can be transmitted peri- is listed in Table 31. natally; through sexual exposure, direct contact with blood, or HBV infection presents as acute hepatitis in a minority of

persons worldwide. See MKSAP 19 General Internal Medicine chronic HBV infection. Interpretation of screening test results 2 for HBV vaccination strategies. HBV can be transmitted peri- is listed in Table 31. natally; through sexual exposure, direct contact with blood, or HBV infection presents as acute hepatitis in a minority of percutaneous exposure; or by close person-to-person contact. patients. Approximately 30% of adults may develop jaundice from The risk for chronic HBV infection decreases with increasing acute infection, with aminotransferase levels as high as 3000 U/L age at time of infection. Newborns acquiring HBV have the and nonspecific symptoms (e.g., malaise, nausea, and right- highest risk (90%), whereas adults have an approximately 5% upper-quadrant pain). Acute liver failure develops in approxi- risk. Screening for HBV infection with hepatitis B surface anti- mately 0.5% of patients. Chronic HBV infection is diagnosed after gen (HBsAg) and antibodies to hepatitis B antigens (anti-HBs 6 months in patients with persistent HBsAg detected in serum. and anti-hepatitis B core antigen [HBc]) is recommended The four phases of chronic HBV infection are differenti- in individuals with risk factors and before initiation of ated on the basis of immune response: immune tolerant, TABLE 31. Interpretation of Hepatitis B Serology Test Results | Interpretation HBsAg Anti-HBs Anti-HBc HBeAg’ Anti-HBe HBVDNA(IU/mL) ALT | 4 Immunized - + = — = - Normal |

| Interpretation HBsAg Anti-HBs Anti-HBc HBeAg’ Anti-HBe HBVDNA(IU/mL) ALT | 4 Immunized - + = — = - Normal | Acute infection + - + (IgM) + - + Increased | Resolved infection = + +(IgG) ~ +/— - Normal Chronic HBV infection Immune tolerant + = +(IgG) + - >1 million Normal or mildly chronic HBV infection elevated Immune active + - +(IgG) + - >2000 HBeAg Increased (intermittent chronic HBV infection negative; >20,000 or persistent) HBeAg positive Inactive chronic + - +(IgG) + <2000 Normal HBV infection (when measured every 3-4 months for 1 year)

Inactive chronic + - +(IgG) + <2000 Normal HBV infection (when measured every 3-4 months for 1 year) ALT = alanine aminotransferase; Anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to hepatitis B e antigen; anti-HBs = antibody to hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus. | Data from Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B:AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560-99. [PMID: 29405329] doi:10.1002/hep.29800. j 54

Vertically Horizontally acquired HBV acquired HBV ' ) Immune tolerant Immune active (HBeAg-positive chronic HBV) (HBeAg-positive or HBeAg-negative chronic HBV) Age <30 years Abnormal ALT Normal ALT Vv HBV DNA >20,000 IU/mL in HBeAg-positive di HBeAg positive, anti-HBe negative HBV DNA >2000 IU/mL in HBeAg-negative disease HBV DNA >1 million Inflammation and fibrosis No inflammation or fibrosis ‘i Immune control (chronic HBV inactive carrier) y Normal ALT Liver injury HBeAg negative, anti-HBe positive HBV DNA <2000 IU/mL JA No inflammation, variable fibrosis

Normal ALT Liver injury HBeAg negative, anti-HBe positive HBV DNA <2000 IU/mL JA No inflammation, variable fibrosis t Reactivation Loss of HBV immune control in patients receiving immunosuppressive therapy Rise in HBV DNA compared to baseline Seroreversion from negative to positive HBsAg for HBsAg-negative, anti-HBc-positive patients FIGURE 30. Phases of chronic hepatitis B virus infection. It is assumed that patients progress through the phases in sequence, although not all patients develop HBeAg- negative chronic hepatitis B, and only patients with vertical transmission of hepatitis B have a clinically recognized immune tolerant phase. All phases feature positivity for HBsAg, negativity for anti-HBs, and positivity for IgG anti-HBc. ALT= alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to hepatitis B e antigen; anti-HBs = antibody to hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HBV DNA= hepatitis B virus DNA.

ALT= alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to hepatitis B e antigen; anti-HBs = antibody to hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HBV DNA= hepatitis B virus DNA. Data obtained from Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on p is, and of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1570. PMID: 29405329 doi:10.1002/hep.29800. immune active, immune control (inactive chronic HBV infec- 48 weeks in patients without cirrhosis who have high ALT tion, which occurs at a rate of 10% per year in previously levels and low HBV DNA levels. immune active patients), and reactivation. Treatment goals for patients in the HBeAg-positive Reactivation of chronic HBV infection results from loss of immune-active phase are HBeAg loss with anti-HBe serocon- immune control in patients with HBsAg-positive/anti-HBc- version, which should then be followed by an additional positive disease or with HBsAg-negative/anti-HBc-positive 12 months of treatment. Goals of treatment in the HBeAg- disease. This often occurs in patients receiving immunosup- negative immune-active phase are HBV DNA suppression and

immune active, immune control (inactive chronic HBV infec- 48 weeks in patients without cirrhosis who have high ALT tion, which occurs at a rate of 10% per year in previously levels and low HBV DNA levels. immune active patients), and reactivation. Treatment goals for patients in the HBeAg-positive Reactivation of chronic HBV infection results from loss of immune-active phase are HBeAg loss with anti-HBe serocon- immune control in patients with HBsAg-positive/anti-HBc- version, which should then be followed by an additional positive disease or with HBsAg-negative/anti-HBc-positive 12 months of treatment. Goals of treatment in the HBeAg- disease. This often occurs in patients receiving immunosup- negative immune-active phase are HBV DNA suppression and pressive therapy. Reactivation is characterized by a rise in HBV ALT normalization; oral antiviral agents are generally contin- DNA compared with baseline and seroconversion from HBsAg ued indefinitely in this setting. HBsAg seroconversion rarely negativity to HBsAg positivity in HBsAg-negative/anti-HBc- occurs with oral antiviral treatment and therefore is not a positive patients. Reactivation may be asymptomatic, result in treatment goal. Patients with cirrhosis should continue oral a hepatitis flare (evidenced by an ALT greater than 100 U/Land antiviral medications indefinitely. more than threefold above baseline), or result in hepatic fail- ure (Figure 30). TABLE 32. Risk Factors for Cirrhosis or Hepatocellular Approximately 40% of deaths in HBV-infected persons Carcinoma in Patients With Chronic Hepatitis B Virus Infection older than 40 years are related to hepatocellular carcinoma or Age >40 years decompensated cirrhosis. Risk factors for these conditions in patients with chronic HBV infection are listed in Table 32; see Hepatitis B virus DNA level >2000 IU/mL

pressive therapy. Reactivation is characterized by a rise in HBV ALT normalization; oral antiviral agents are generally contin- DNA compared with baseline and seroconversion from HBsAg ued indefinitely in this setting. HBsAg seroconversion rarely negativity to HBsAg positivity in HBsAg-negative/anti-HBc- occurs with oral antiviral treatment and therefore is not a positive patients. Reactivation may be asymptomatic, result in treatment goal. Patients with cirrhosis should continue oral a hepatitis flare (evidenced by an ALT greater than 100 U/Land antiviral medications indefinitely. more than threefold above baseline), or result in hepatic fail- ure (Figure 30). TABLE 32. Risk Factors for Cirrhosis or Hepatocellular Approximately 40% of deaths in HBV-infected persons Carcinoma in Patients With Chronic Hepatitis B Virus Infection older than 40 years are related to hepatocellular carcinoma or Age >40 years decompensated cirrhosis. Risk factors for these conditions in patients with chronic HBV infection are listed in Table 32; see Hepatitis B virus DNA level >2000 IU/mL Hepatocellular Carcinoma for recommendations on hepato- Elevated alanine aminotransferase level

pressive therapy. Reactivation is characterized by a rise in HBV ALT normalization; oral antiviral agents are generally contin- DNA compared with baseline and seroconversion from HBsAg ued indefinitely in this setting. HBsAg seroconversion rarely negativity to HBsAg positivity in HBsAg-negative/anti-HBc- occurs with oral antiviral treatment and therefore is not a positive patients. Reactivation may be asymptomatic, result in treatment goal. Patients with cirrhosis should continue oral a hepatitis flare (evidenced by an ALT greater than 100 U/Land antiviral medications indefinitely. more than threefold above baseline), or result in hepatic fail- ure (Figure 30). TABLE 32. Risk Factors for Cirrhosis or Hepatocellular Approximately 40% of deaths in HBV-infected persons Carcinoma in Patients With Chronic Hepatitis B Virus Infection older than 40 years are related to hepatocellular carcinoma or Age >40 years decompensated cirrhosis. Risk factors for these conditions in patients with chronic HBV infection are listed in Table 32; see Hepatitis B virus DNA level >2000 IU/mL Hepatocellular Carcinoma for recommendations on hepato- Elevated alanine aminotransferase level cellular carcinoma screening and surveillance. GenotypeC infection Treatment is advised for patients with acute liver failure, Heavy alcohol use infection in the immune-active phase or reactivation phase, Development of hepatitis B e antigen-negative reactivation and cirrhosis as well as in selected immunosuppressed phase of chronic hepatitis B virus infection patients. First-line treatment is entecavir or tenofovir. HIV infection Lamivudine, adefovir, and telbivudine are less commonly used Hepatitis C virus or hepatitis D virus infection | because of resistance. Pegylated interferon can be used for

cellular carcinoma screening and surveillance. GenotypeC infection Treatment is advised for patients with acute liver failure, Heavy alcohol use infection in the immune-active phase or reactivation phase, Development of hepatitis B e antigen-negative reactivation and cirrhosis as well as in selected immunosuppressed phase of chronic hepatitis B virus infection patients. First-line treatment is entecavir or tenofovir. HIV infection Lamivudine, adefovir, and telbivudine are less commonly used Hepatitis C virus or hepatitis D virus infection | because of resistance. Pegylated interferon can be used for 55

Disorders of the Liver Prophylactic oral antiviral therapy should be given to and RNA results have active infection and should undergo patients who are HBsAg-positive or isolated core antibody— genotyping.

Disorders of the Liver Prophylactic oral antiviral therapy should be given to and RNA results have active infection and should undergo patients who are HBsAg-positive or isolated core antibody— genotyping. positive and are receiving B-cell-depleting therapy (e.g., ritux- Acute HCV infection is usually asymptomatic, but jaun- imab or ofatumumab), prednisone (210 mg/d for at least dice, nausea, right-upper-quadrant pain, dark urine, and 4 weeks), or anthracycline derivatives. Patients receiving acholic stools can occur. Evaluation of suspected acute infec- tumor necrosis factor-a or tyrosine kinase inhibitors should tion includes HCV antibody and RNA tests. The HCV RNA also be considered for prophylaxis. result becomes positive first, followed by HCV antibody within Rarely, patients with HBV infection develop membranous 12 weeks of infection. The antibody remains positive for life nephropathy, membranoproliferative nephropathy, polyarteri- but does not confer immunity from reinfection. Spontaneous tis nodosa, or cryoglobulinemia, all of which should prompt clearance (usually within 6 months) is more common in oral antiviral therapy. women, younger patients, and patients with symptoms, high The survival rate after liver transplantation for end stage ALT levels, or the IL-28 CC genotype. Monitoring HCV RNA liver disease from HBV infection is greater than 90% at 1 year. levels for clearance at 3 and 6 months is recommended in Recurrence of HBV infection in transplant recipients is prevented patients with acute infection. with HBV immunoglobulin and/or oral antiviral therapy. HCV results in chronic infection in 60% to 80% ofpatients; up to 30% progress to cirrhosis over two to three decades. Risk Hepatitis C for hepatocellular carcinoma in patients with cirrhosis is 2% to

positive and are receiving B-cell-depleting therapy (e.g., ritux- Acute HCV infection is usually asymptomatic, but jaun- imab or ofatumumab), prednisone (210 mg/d for at least dice, nausea, right-upper-quadrant pain, dark urine, and 4 weeks), or anthracycline derivatives. Patients receiving acholic stools can occur. Evaluation of suspected acute infec- tumor necrosis factor-a or tyrosine kinase inhibitors should tion includes HCV antibody and RNA tests. The HCV RNA also be considered for prophylaxis. result becomes positive first, followed by HCV antibody within Rarely, patients with HBV infection develop membranous 12 weeks of infection. The antibody remains positive for life nephropathy, membranoproliferative nephropathy, polyarteri- but does not confer immunity from reinfection. Spontaneous tis nodosa, or cryoglobulinemia, all of which should prompt clearance (usually within 6 months) is more common in oral antiviral therapy. women, younger patients, and patients with symptoms, high The survival rate after liver transplantation for end stage ALT levels, or the IL-28 CC genotype. Monitoring HCV RNA liver disease from HBV infection is greater than 90% at 1 year. levels for clearance at 3 and 6 months is recommended in Recurrence of HBV infection in transplant recipients is prevented patients with acute infection. with HBV immunoglobulin and/or oral antiviral therapy. HCV results in chronic infection in 60% to 80% ofpatients; up to 30% progress to cirrhosis over two to three decades. Risk Hepatitis C for hepatocellular carcinoma in patients with cirrhosis is 2% to Worldwide, approximately 150 million individuals are infected 4% per year.

positive and are receiving B-cell-depleting therapy (e.g., ritux- Acute HCV infection is usually asymptomatic, but jaun- imab or ofatumumab), prednisone (210 mg/d for at least dice, nausea, right-upper-quadrant pain, dark urine, and 4 weeks), or anthracycline derivatives. Patients receiving acholic stools can occur. Evaluation of suspected acute infec- tumor necrosis factor-a or tyrosine kinase inhibitors should tion includes HCV antibody and RNA tests. The HCV RNA also be considered for prophylaxis. result becomes positive first, followed by HCV antibody within Rarely, patients with HBV infection develop membranous 12 weeks of infection. The antibody remains positive for life nephropathy, membranoproliferative nephropathy, polyarteri- but does not confer immunity from reinfection. Spontaneous tis nodosa, or cryoglobulinemia, all of which should prompt clearance (usually within 6 months) is more common in oral antiviral therapy. women, younger patients, and patients with symptoms, high The survival rate after liver transplantation for end stage ALT levels, or the IL-28 CC genotype. Monitoring HCV RNA liver disease from HBV infection is greater than 90% at 1 year. levels for clearance at 3 and 6 months is recommended in Recurrence of HBV infection in transplant recipients is prevented patients with acute infection. with HBV immunoglobulin and/or oral antiviral therapy. HCV results in chronic infection in 60% to 80% ofpatients; up to 30% progress to cirrhosis over two to three decades. Risk Hepatitis C for hepatocellular carcinoma in patients with cirrhosis is 2% to Worldwide, approximately 150 million individuals are infected 4% per year. with hepatitis C virus (HCV). HCV is most commonly trans- Several extrahepatic diseases are associated with chronic

positive and are receiving B-cell-depleting therapy (e.g., ritux- Acute HCV infection is usually asymptomatic, but jaun- imab or ofatumumab), prednisone (210 mg/d for at least dice, nausea, right-upper-quadrant pain, dark urine, and 4 weeks), or anthracycline derivatives. Patients receiving acholic stools can occur. Evaluation of suspected acute infec- tumor necrosis factor-a or tyrosine kinase inhibitors should tion includes HCV antibody and RNA tests. The HCV RNA also be considered for prophylaxis. result becomes positive first, followed by HCV antibody within Rarely, patients with HBV infection develop membranous 12 weeks of infection. The antibody remains positive for life nephropathy, membranoproliferative nephropathy, polyarteri- but does not confer immunity from reinfection. Spontaneous tis nodosa, or cryoglobulinemia, all of which should prompt clearance (usually within 6 months) is more common in oral antiviral therapy. women, younger patients, and patients with symptoms, high The survival rate after liver transplantation for end stage ALT levels, or the IL-28 CC genotype. Monitoring HCV RNA liver disease from HBV infection is greater than 90% at 1 year. levels for clearance at 3 and 6 months is recommended in Recurrence of HBV infection in transplant recipients is prevented patients with acute infection. with HBV immunoglobulin and/or oral antiviral therapy. HCV results in chronic infection in 60% to 80% ofpatients; up to 30% progress to cirrhosis over two to three decades. Risk Hepatitis C for hepatocellular carcinoma in patients with cirrhosis is 2% to Worldwide, approximately 150 million individuals are infected 4% per year. with hepatitis C virus (HCV). HCV is most commonly trans- Several extrahepatic diseases are associated with chronic mitted through intravenous or intranasal drug use, blood HCV infection, including non-Hodgkin lymphoma, mem-

Worldwide, approximately 150 million individuals are infected 4% per year. with hepatitis C virus (HCV). HCV is most commonly trans- Several extrahepatic diseases are associated with chronic mitted through intravenous or intranasal drug use, blood HCV infection, including non-Hodgkin lymphoma, mem- transfusions before 1992, or sexual intercourse, although the branoproliferative glomerulonephritis, and mixed cryoglobu efficiency of viral spread through vaginal intercourse is low. All linemia. Chronic HCV infection is also the most common patients aged 18 to 79 years should be screened for HCV, fol- cause of porphyria cutanea tarda, although it is also associ- lowed by HCV RNA testing if those results are positive. ated with alcohol-induced liver damage and hemochroma Although guidelines from the U.S. Preventive Services Task tosis. It presents with increased skin fragility noted on Force suggest not screening patients older than 79 years in the sun exposed areas, most frequently the dorsal hands. Small absence of specific risk factors, the CDC does not specify an vesicles rupture, leaving erosions (Figure 31). Treatment of upper age limit. Other patients with risk factors may also porphyria cutanea tarda is aimed at avoiding sun exposure require testing (Table 33). Patients with positive HCV antibody TABLE 33. Conditions Requiring Testing for Hepatitis C Virus Age 18-79 years? Injection-drug use or intranasal illicit-drug use (ever) Long-term hemodialysis (ever) Percutaneous/parenteral exposures in an unregulated setting (nonsterile technique) Needlesticks, sharps, or mucosal exposure to hepatitis C virus- | infected blood Children born to women infected with hepatitis C virus Receipt of blood or blood-components transfusion or organ transplantation before 1992 Receipt of clotting-factor concentrates produced before 1987 History of incarceration HIV infection Sexually active persons about to start pre-exposure prophylaxis for HIV Undiagnosed chronic liver disease Elevated alanine aminotransferase level Living organ donors before donation

Receipt of blood or blood-components transfusion or organ transplantation before 1992 Receipt of clotting-factor concentrates produced before 1987 History of incarceration HIV infection Sexually active persons about to start pre-exposure prophylaxis for HIV Undiagnosed chronic liver disease Elevated alanine aminotransferase level Living organ donors before donation “This age range is recommended in guidelines from the U.S. Preventive Services | FIGURE 31. Porphyria cutanea tarda manifests as a chronic blistering disease Task Force. The CDC does not specify an upper age limit for screening. | with epidermal erosions on sun-exposed skin, especially on the backs of the hands. 56

Disorders of the Liver and decreasing iron overload with phlebotomy; low-dose to chronic liver disease (in the case of simultaneous HBV-HDV hydroxychloroquine is a second-line option. co-infection) and to fulminant hepatitis in HDV superinfec- All HCV-infected patients should be tested for HBV (see tion in a patient with previous HBV infection. HDV-infected Hepatitis B section for further discussion) because of the patients with evidence of progressive liver disease should potential shared routes of transmission. Susceptible patients receive 12-month pegylated interferon treatment; cure rates should receive HBV vaccination. HBV can be reactivated dur- are 25% to 45%. ing direct-acting antiviral therapy for HCV infection. Patients who test positive for HBsAg with detectable HBV DNA and Hepatitis E who do not meet standard HBV treatment criteria should Hepatitis E virus (HEV) is an RNA virus with worldwide distri- undergo HBV DNA monitoring approximately every 4 weeks bution. There are four genotypes: Genotypes 1 and 2 are more until 12 weeks after completion of HCV treatment, or they can common in developing countries and are transmitted by the receive oral HBV therapy prophylactically. fecal-oral route through contaminated water; genotypes 3 and All HCV-infected patients except those with a short life 4 are more common in developed countries, where transmis- expectancy should be considered for treatment. Patients with sion occurs through contaminated food, mostly pork or veni- decompensated cirrhosis should see a hepatologist before son. In developing countries, HEV infection generally occurs treatment and be considered for liver transplantation. in young adults and can occur in large epidemics. In developed Patients being considered for treatment require a pre- countries, HEV usually affects men older than 40 years. The treatment fibrosis assessment (see Approach to the Patient incubation period is 2 to 5 weeks. Approximately 50% of cases With Abnormal Liver Chemistry Studies). Noninvasive assess- are asymptomatic. Symptoms of HEV infection are jaundice, ment using fibrosis serologic biomarkers and/or elastography malaise, nausea, vomiting, anorexia, and right-upper- is preferred unless patients have a documented short duration quadrant pain. Aminotransferase levels are usually elevated to of disease, decompensated cirrhosis, or a radiologic diagnosis 1000 to 3000 U/L. Diagnosis relies on detecting HEV IgM or of cirrhosis. Routine liver biopsy for pretreatment fibrosis RNA. Treatment is supportive, and recovery is expected in 4 to assessment is not recommended. 6 weeks. Chronic HEV infection is typically seen only in immu- Treatment regimens include a combination of direct- nocompromised patients. HEV infection should be considered acting antivirals with the use of different mechanisms to pre- in patients with an unknown cause of acute hepatitis and in vent viral reproduction. Regimens are chosen based on immunocompromised patients with chronic hepatitis. Solid- genotype, treatment experience and response, and fibrosis organ transplant recipients with chronic HEV infection may status (current recommendations on HCV treatment regimens require ribavirin treatment and have response rates of 70%. can be found at www.hevguidelines.org). Patients are often managed by a hepatologist or infectious disease specialist Other Viruses because retreatment guided by resistance-associated substitu- Other viruses can cause hepatitis. These viruses along with tion may be necessary. their symptoms, laboratory findings, and treatment options Cure rates exceed 90% in most patients. Cure is defined are listed in Table 34. by no HCV RNA in blood 12 weeks after treatment ends. HCV antibody positivity remains indefinitely and should not be rechecked. Patients can become reinfected after new ¢ Treatment of hepatitis A virus infection is supportive, and exposures, and HCV RNA testing is appropriate to identify 90% of patients or more recover fully within 3 to 6 months new infection. Virologic cure reduces risk for progression to of infection. cirrhosis, complications of cirrhosis, hepatocellular carci- e Treatment of hepatitis B virus infection is advised for noma, and liver-related mortality. Patients with advanced patients with acute liver failure, infection in the immune- (METAVIR stage F3) fibrosis require ongoing surveillance for active phase or the reactivation phase, and cirrhosis, hepatocellular carcinoma even after virologic cure. Patients and for immunosuppressed patients. with cryoglobulinemic vasculitis and non-Hodgkin lym- phoma are more likely to experience remission when HCV e All patients aged 18 to 79 years should be screened for

and decreasing iron overload with phlebotomy; low-dose to chronic liver disease (in the case of simultaneous HBV-HDV hydroxychloroquine is a second-line option. co-infection) and to fulminant hepatitis in HDV superinfec- All HCV-infected patients should be tested for HBV (see tion in a patient with previous HBV infection. HDV-infected Hepatitis B section for further discussion) because of the patients with evidence of progressive liver disease should potential shared routes of transmission. Susceptible patients receive 12-month pegylated interferon treatment; cure rates should receive HBV vaccination. HBV can be reactivated dur- are 25% to 45%. ing direct-acting antiviral therapy for HCV infection. Patients who test positive for HBsAg with detectable HBV DNA and Hepatitis E who do not meet standard HBV treatment criteria should Hepatitis E virus (HEV) is an RNA virus with worldwide distri- undergo HBV DNA monitoring approximately every 4 weeks bution. There are four genotypes: Genotypes 1 and 2 are more until 12 weeks after completion of HCV treatment, or they can common in developing countries and are transmitted by the receive oral HBV therapy prophylactically. fecal-oral route through contaminated water; genotypes 3 and All HCV-infected patients except those with a short life 4 are more common in developed countries, where transmis- expectancy should be considered for treatment. Patients with sion occurs through contaminated food, mostly pork or veni- decompensated cirrhosis should see a hepatologist before son. In developing countries, HEV infection generally occurs treatment and be considered for liver transplantation. in young adults and can occur in large epidemics. In developed Patients being considered for treatment require a pre- countries, HEV usually affects men older than 40 years. The treatment fibrosis assessment (see Approach to the Patient incubation period is 2 to 5 weeks. Approximately 50% of cases With Abnormal Liver Chemistry Studies). Noninvasive assess- are asymptomatic. Symptoms of HEV infection are jaundice, ment using fibrosis serologic biomarkers and/or elastography malaise, nausea, vomiting, anorexia, and right-upper- is preferred unless patients have a documented short duration quadrant pain. Aminotransferase levels are usually elevated to of disease, decompensated cirrhosis, or a radiologic diagnosis 1000 to 3000 U/L. Diagnosis relies on detecting HEV IgM or of cirrhosis. Routine liver biopsy for pretreatment fibrosis RNA. Treatment is supportive, and recovery is expected in 4 to assessment is not recommended. 6 weeks. Chronic HEV infection is typically seen only in immu- Treatment regimens include a combination of direct- nocompromised patients. HEV infection should be considered acting antivirals with the use of different mechanisms to pre- in patients with an unknown cause of acute hepatitis and in vent viral reproduction. Regimens are chosen based on immunocompromised patients with chronic hepatitis. Solid- genotype, treatment experience and response, and fibrosis organ transplant recipients with chronic HEV infection may status (current recommendations on HCV treatment regimens require ribavirin treatment and have response rates of 70%. can be found at www.hevguidelines.org). Patients are often managed by a hepatologist or infectious disease specialist Other Viruses because retreatment guided by resistance-associated substitu- Other viruses can cause hepatitis. These viruses along with tion may be necessary. their symptoms, laboratory findings, and treatment options Cure rates exceed 90% in most patients. Cure is defined are listed in Table 34. by no HCV RNA in blood 12 weeks after treatment ends. HCV antibody positivity remains indefinitely and should not be rechecked. Patients can become reinfected after new ¢ Treatment of hepatitis A virus infection is supportive, and exposures, and HCV RNA testing is appropriate to identify 90% of patients or more recover fully within 3 to 6 months new infection. Virologic cure reduces risk for progression to of infection. cirrhosis, complications of cirrhosis, hepatocellular carci- e Treatment of hepatitis B virus infection is advised for noma, and liver-related mortality. Patients with advanced patients with acute liver failure, infection in the immune- (METAVIR stage F3) fibrosis require ongoing surveillance for active phase or the reactivation phase, and cirrhosis, hepatocellular carcinoma even after virologic cure. Patients and for immunosuppressed patients. with cryoglobulinemic vasculitis and non-Hodgkin lym- phoma are more likely to experience remission when HCV e All patients aged 18 to 79 years should be screened for is eradicated. HCV followed by HCV RNA testing if the results are positive.

and decreasing iron overload with phlebotomy; low-dose to chronic liver disease (in the case of simultaneous HBV-HDV hydroxychloroquine is a second-line option. co-infection) and to fulminant hepatitis in HDV superinfec- All HCV-infected patients should be tested for HBV (see tion in a patient with previous HBV infection. HDV-infected Hepatitis B section for further discussion) because of the patients with evidence of progressive liver disease should potential shared routes of transmission. Susceptible patients receive 12-month pegylated interferon treatment; cure rates should receive HBV vaccination. HBV can be reactivated dur- are 25% to 45%. ing direct-acting antiviral therapy for HCV infection. Patients who test positive for HBsAg with detectable HBV DNA and Hepatitis E who do not meet standard HBV treatment criteria should Hepatitis E virus (HEV) is an RNA virus with worldwide distri- undergo HBV DNA monitoring approximately every 4 weeks bution. There are four genotypes: Genotypes 1 and 2 are more until 12 weeks after completion of HCV treatment, or they can common in developing countries and are transmitted by the receive oral HBV therapy prophylactically. fecal-oral route through contaminated water; genotypes 3 and All HCV-infected patients except those with a short life 4 are more common in developed countries, where transmis- expectancy should be considered for treatment. Patients with sion occurs through contaminated food, mostly pork or veni- decompensated cirrhosis should see a hepatologist before son. In developing countries, HEV infection generally occurs treatment and be considered for liver transplantation. in young adults and can occur in large epidemics. In developed Patients being considered for treatment require a pre- countries, HEV usually affects men older than 40 years. The treatment fibrosis assessment (see Approach to the Patient incubation period is 2 to 5 weeks. Approximately 50% of cases With Abnormal Liver Chemistry Studies). Noninvasive assess- are asymptomatic. Symptoms of HEV infection are jaundice, ment using fibrosis serologic biomarkers and/or elastography malaise, nausea, vomiting, anorexia, and right-upper- is preferred unless patients have a documented short duration quadrant pain. Aminotransferase levels are usually elevated to of disease, decompensated cirrhosis, or a radiologic diagnosis 1000 to 3000 U/L. Diagnosis relies on detecting HEV IgM or of cirrhosis. Routine liver biopsy for pretreatment fibrosis RNA. Treatment is supportive, and recovery is expected in 4 to assessment is not recommended. 6 weeks. Chronic HEV infection is typically seen only in immu- Treatment regimens include a combination of direct- nocompromised patients. HEV infection should be considered acting antivirals with the use of different mechanisms to pre- in patients with an unknown cause of acute hepatitis and in vent viral reproduction. Regimens are chosen based on immunocompromised patients with chronic hepatitis. Solid- genotype, treatment experience and response, and fibrosis organ transplant recipients with chronic HEV infection may status (current recommendations on HCV treatment regimens require ribavirin treatment and have response rates of 70%. can be found at www.hevguidelines.org). Patients are often managed by a hepatologist or infectious disease specialist Other Viruses because retreatment guided by resistance-associated substitu- Other viruses can cause hepatitis. These viruses along with tion may be necessary. their symptoms, laboratory findings, and treatment options Cure rates exceed 90% in most patients. Cure is defined are listed in Table 34. by no HCV RNA in blood 12 weeks after treatment ends. HCV antibody positivity remains indefinitely and should not be rechecked. Patients can become reinfected after new ¢ Treatment of hepatitis A virus infection is supportive, and exposures, and HCV RNA testing is appropriate to identify 90% of patients or more recover fully within 3 to 6 months new infection. Virologic cure reduces risk for progression to of infection. cirrhosis, complications of cirrhosis, hepatocellular carci- e Treatment of hepatitis B virus infection is advised for noma, and liver-related mortality. Patients with advanced patients with acute liver failure, infection in the immune- (METAVIR stage F3) fibrosis require ongoing surveillance for active phase or the reactivation phase, and cirrhosis, hepatocellular carcinoma even after virologic cure. Patients and for immunosuppressed patients. with cryoglobulinemic vasculitis and non-Hodgkin lym- phoma are more likely to experience remission when HCV e All patients aged 18 to 79 years should be screened for is eradicated. HCV followed by HCV RNA testing if the results are positive. e All hepatitis C virus-infected patients except those with Hepatitis D a short life expectancy should be considered for treatment; Hepatitis D virus (HDV) is a defective RNA virus that requires cure rates exceed 90% in most patients. concurrent infection with HBV for human infection. HDV e Hepatitis E virus infection should be considered in infection is endemic in the Mediterranean basin and Pacific patients with an unknown cause of acute hepatitis islands and uncommon in Western countries. It is diagnosed and in immunocompromised patients with chronic through detection of HDV IgG. The clinical course ranges from hepatitis. inactive disease to acute hepatitis, with occasional progression

e All hepatitis C virus-infected patients except those with Hepatitis D a short life expectancy should be considered for treatment; Hepatitis D virus (HDV) is a defective RNA virus that requires cure rates exceed 90% in most patients. concurrent infection with HBV for human infection. HDV e Hepatitis E virus infection should be considered in infection is endemic in the Mediterranean basin and Pacific patients with an unknown cause of acute hepatitis islands and uncommon in Western countries. It is diagnosed and in immunocompromised patients with chronic through detection of HDV IgG. The clinical course ranges from hepatitis. inactive disease to acute hepatitis, with occasional progression 57

Disorders of the Liver TABLE 34. Other Viral Causes of Hepatitis? Infection Symptoms/Laboratory Diagnosis Treatment/Outcome Findings Cytomegalovirus Mimics EBV-related CMV serologies in Supportive; spontaneous mononucleosis immunocompetent host recovery is norm Mild aminotransferase elevations Primary herpes simplex virus Fever, altered mental status, PCR; herpes simplex virus IV acyclovir; 80% case-fatality in women in third trimester of right-upper-quadrant pain, testing; liver biopsy showing rate in untreated patients pregnancy hepatomegaly, presentation intranuclear inclusions, similar to sepsis multinucleated giant cells, and coagulative necrosis with Aminotransferase levels minimal inflammation 25000 U/L, disproportionately low bilirubin level, coagulopathy Primary varicella zoster virus Primary infection in organ Biopsy of skin or affected organ IV acyclovir (rare) transplant recipients can cause acute liver failure

Primary herpes simplex virus Fever, altered mental status, PCR; herpes simplex virus IV acyclovir; 80% case-fatality in women in third trimester of right-upper-quadrant pain, testing; liver biopsy showing rate in untreated patients pregnancy hepatomegaly, presentation intranuclear inclusions, similar to sepsis multinucleated giant cells, and coagulative necrosis with Aminotransferase levels minimal inflammation 25000 U/L, disproportionately low bilirubin level, coagulopathy Primary varicella zoster virus Primary infection in organ Biopsy of skin or affected organ IV acyclovir (rare) transplant recipients can cause acute liver failure Parvovirus B19 Fever, rash, arthralgias Serologic tests demonstrating Supportive; rarely associated positivity for parvovirus B19- with fulminant hepatic failure | | Transiently elevated specific IgM antibody aminotransferase levels CMV = cytomegalovirus; EBV = Epstein-Barr virus; IV = intravenous; PCR = polymerase chain reaction. °Other viruses associated with elevated liver chemistries: human herpes virus 6, 7, and 8 and adenoviruses. Autoimmune Hepatitis Autoimmune hepatitis is a chronic inflammatory hepatitis e Diagnosis of autoimmune hepatitis is based on elevated

CMV = cytomegalovirus; EBV = Epstein-Barr virus; IV = intravenous; PCR = polymerase chain reaction. °Other viruses associated with elevated liver chemistries: human herpes virus 6, 7, and 8 and adenoviruses. Autoimmune Hepatitis Autoimmune hepatitis is a chronic inflammatory hepatitis e Diagnosis of autoimmune hepatitis is based on elevated that is four times more common in women than men and can aminotransferase levels, positivity for antinuclear anti- be associated with other autoimmune diseases (autoimmune body and smooth muscle antibody, elevated levels of thyroiditis, rheumatoid arthritis, or ulcerative colitis). It can IgG, and liver histology.

that is four times more common in women than men and can aminotransferase levels, positivity for antinuclear anti- be associated with other autoimmune diseases (autoimmune body and smooth muscle antibody, elevated levels of thyroiditis, rheumatoid arthritis, or ulcerative colitis). It can IgG, and liver histology. affect individuals at any age but most frequently occurs in e Treatment of autoimmune hepatitis includes a combina- middle aged adults. Presentation of autoimmune hepatitis tion of prednisone and azathioprine for most patients; varies from asymptomatic elevation of aminotransferase levels duration of treatment should be 2 to 3 years before con to extrahepatic symptoms, such as myalgia and malaise, to sideration of withdrawal. acute liver failure. Diagnosis is based on laboratory results (including positivity for antinuclear and smooth-muscle anti- bodies and elevated IgG levels), exclusion of other diagnoses Alcohol-Induced Liver Disease (e.g., Wilson disease, viral hepatitis, and drug-induced liver Alcohol injury to the liver may take the form of steatosis, stea- injury), and liver histology. tohepatitis, fibrosis, or cirrhosis. A history of alcohol use is the Treatment includes a combination of prednisone and most important component in making the diagnosis, although azathioprine for most patients. Prednisone monotherapy not all patients are forthcoming about alcohol use. See MKSAP may be less preferable because of adverse effects, although 19 General Internal Medicine 2 for more information about azathioprine requires monitoring for cytopenia and may screening for alcohol use disorder. Most patients with alco- cause drug-induced hepatitis. Biochemical response holic liver disease have consumed more than 100 g of alcohol occurs in 3 to 8 months for the 85% of patients whose dis- daily for 20 years. Alcoholic hepatitis is a distinct clinical syn ease responds to standard treatment, but histologic drome of severe steatohepatitis on a background of chronic response can lag by many months. Duration of treatment alcoholic liver disease, often presenting with fever, jaundice, should be 2 to 3 years before consideration of withdrawal. tender hepatomegaly, and leukocytosis. Approximately 25% of Liver biopsy is recommended to determine histologic heavy drinkers develop cirrhosis. Differentiating alcoholic response before consideration of drug withdrawal. High hepatitis from decompensated cirrhosis in patients with relapse rates after discontinuation of treatment under- underlying cirrhosis can be difficult. score the need for serial monitoring of liver tests. Patients Physical examination may show evidence of hepatomeg- with severe acute autoimmune hepatitis presenting with aly in patients with steatosis or steatohepatitis. In patients jaundice should be managed by a hepatologist, and patients with alcoholic hepatitis or cirrhosis, findings of advanced liver with features of acute liver failure require urgent transfer disease may be present, including muscle wasting, scleral to a transplant center. icterus, jaundice (including sublingual jaundice), spider

affect individuals at any age but most frequently occurs in e Treatment of autoimmune hepatitis includes a combina- middle aged adults. Presentation of autoimmune hepatitis tion of prednisone and azathioprine for most patients; varies from asymptomatic elevation of aminotransferase levels duration of treatment should be 2 to 3 years before con to extrahepatic symptoms, such as myalgia and malaise, to sideration of withdrawal. acute liver failure. Diagnosis is based on laboratory results (including positivity for antinuclear and smooth-muscle anti- bodies and elevated IgG levels), exclusion of other diagnoses Alcohol-Induced Liver Disease (e.g., Wilson disease, viral hepatitis, and drug-induced liver Alcohol injury to the liver may take the form of steatosis, stea- injury), and liver histology. tohepatitis, fibrosis, or cirrhosis. A history of alcohol use is the Treatment includes a combination of prednisone and most important component in making the diagnosis, although azathioprine for most patients. Prednisone monotherapy not all patients are forthcoming about alcohol use. See MKSAP may be less preferable because of adverse effects, although 19 General Internal Medicine 2 for more information about azathioprine requires monitoring for cytopenia and may screening for alcohol use disorder. Most patients with alco- cause drug-induced hepatitis. Biochemical response holic liver disease have consumed more than 100 g of alcohol occurs in 3 to 8 months for the 85% of patients whose dis- daily for 20 years. Alcoholic hepatitis is a distinct clinical syn ease responds to standard treatment, but histologic drome of severe steatohepatitis on a background of chronic response can lag by many months. Duration of treatment alcoholic liver disease, often presenting with fever, jaundice, should be 2 to 3 years before consideration of withdrawal. tender hepatomegaly, and leukocytosis. Approximately 25% of Liver biopsy is recommended to determine histologic heavy drinkers develop cirrhosis. Differentiating alcoholic response before consideration of drug withdrawal. High hepatitis from decompensated cirrhosis in patients with relapse rates after discontinuation of treatment under- underlying cirrhosis can be difficult. score the need for serial monitoring of liver tests. Patients Physical examination may show evidence of hepatomeg- with severe acute autoimmune hepatitis presenting with aly in patients with steatosis or steatohepatitis. In patients jaundice should be managed by a hepatologist, and patients with alcoholic hepatitis or cirrhosis, findings of advanced liver with features of acute liver failure require urgent transfer disease may be present, including muscle wasting, scleral to a transplant center. icterus, jaundice (including sublingual jaundice), spider 58

Disorders of the Liver angiomata, gynecomastia, testicular atrophy, or palmar ery- hypertension and a history of consistent alcohol intake. Liver thema. Laboratory evaluation of alcohol-induced liver disease biopsy is sometimes necessary in cases with diagnostic ambi may show an elevated mean corpuscular volume, AST-to-ALT guity. In patients who drink alcohol, liver inflammation ratio greater than 2, elevated y-glutamyl transferase level, ele- increases stiffness, making elastography inaccurate. Nutritional

angiomata, gynecomastia, testicular atrophy, or palmar ery- hypertension and a history of consistent alcohol intake. Liver thema. Laboratory evaluation of alcohol-induced liver disease biopsy is sometimes necessary in cases with diagnostic ambi may show an elevated mean corpuscular volume, AST-to-ALT guity. In patients who drink alcohol, liver inflammation ratio greater than 2, elevated y-glutamyl transferase level, ele- increases stiffness, making elastography inaccurate. Nutritional vated phosphatidyl ethanol level, and, in advanced cases, ele- assessments and alcohol treatment are required. Alcohol absti- vated INR and thrombocytopenia. The IgA level may be elevated. nence can result in significant stabilization of liver function The Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease and reversal of portal hypertension. Patients with alcoholic Index (www.mayoclinic.org/medical-professionals/model- liver disease and evidence of cirrhosis with or without portal end-stage-liver-disease/alcoholic-liver-disease-nonalcoholic- hypertension should be referred to hepatology for further man- fatty-liver-disease-index) can help distinguish alcoholic liver agement and consideration of liver transplantation, regardless disease from nonalcoholic fatty liver disease. The predictive of duration of alcohol abstinence. Aleohol-induced liver disease model is based on AST, ALT, mean corpuscular volume, age, is the second most common reason for liver transplantation in height, weight, and sex. the United States, behind HCV. Alcoholic hepatitis is most often diagnosed clinically, with liver biopsy reserved for diagnostic uncertainty. Severity of e The Alcoholic Liver Disease/Nonalcoholic Fatty Liver alcoholic hepatitis can be determined by the Maddrey discri- Disease Index can help distinguish alcoholic liver disease minant function (MDF) score, which is calculated as follows: from nonalcoholic fatty liver disease. MDF score = 4.6 (prothrombin time [s] e Manifestations of alcoholic hepatitis include fever. jaundice, - control prothrombin time [s]) tender hepatomegaly, and leukocytosis. + total bilirubin (mg/dL) ® Severity of alcoholic hepatitis is determined by the The Model for End-Stage Liver Disease (MELD) score (https:// Maddrey discriminant function (MDF) score and Modified optn.transplant.hrsa.gov/resources/allocation-calculators/meld- End Stage Liver Disease (MELD) score: patients with an calculator/) can also be used to assess severity, with a MELD MDF score of 32 or greater, MELD score greater than 20, score greater than 20 suggesting moderate to severe disease. or hepatic encephalopathy may be considered for predni- (See Classification of Liver Disease Severity for additional solone therapy. details on components of this score.) e Pentoxifylline is no longer recommended for treatment In severe cases (MDF score 232, MELD score >20, or of alcoholic hepatitis. hepatic encephalopathy), treatment with prednisolone (which does not require hepatic metabolism, unlike prednisone) is e All patients with advanced alcoholic liver disease should

vated phosphatidyl ethanol level, and, in advanced cases, ele- assessments and alcohol treatment are required. Alcohol absti- vated INR and thrombocytopenia. The IgA level may be elevated. nence can result in significant stabilization of liver function The Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease and reversal of portal hypertension. Patients with alcoholic Index (www.mayoclinic.org/medical-professionals/model- liver disease and evidence of cirrhosis with or without portal end-stage-liver-disease/alcoholic-liver-disease-nonalcoholic- hypertension should be referred to hepatology for further man- fatty-liver-disease-index) can help distinguish alcoholic liver agement and consideration of liver transplantation, regardless disease from nonalcoholic fatty liver disease. The predictive of duration of alcohol abstinence. Aleohol-induced liver disease model is based on AST, ALT, mean corpuscular volume, age, is the second most common reason for liver transplantation in height, weight, and sex. the United States, behind HCV. Alcoholic hepatitis is most often diagnosed clinically, with liver biopsy reserved for diagnostic uncertainty. Severity of e The Alcoholic Liver Disease/Nonalcoholic Fatty Liver alcoholic hepatitis can be determined by the Maddrey discri- Disease Index can help distinguish alcoholic liver disease minant function (MDF) score, which is calculated as follows: from nonalcoholic fatty liver disease. MDF score = 4.6 (prothrombin time [s] e Manifestations of alcoholic hepatitis include fever. jaundice, - control prothrombin time [s]) tender hepatomegaly, and leukocytosis. + total bilirubin (mg/dL) ® Severity of alcoholic hepatitis is determined by the The Model for End-Stage Liver Disease (MELD) score (https:// Maddrey discriminant function (MDF) score and Modified optn.transplant.hrsa.gov/resources/allocation-calculators/meld- End Stage Liver Disease (MELD) score: patients with an calculator/) can also be used to assess severity, with a MELD MDF score of 32 or greater, MELD score greater than 20, score greater than 20 suggesting moderate to severe disease. or hepatic encephalopathy may be considered for predni- (See Classification of Liver Disease Severity for additional solone therapy. details on components of this score.) e Pentoxifylline is no longer recommended for treatment In severe cases (MDF score 232, MELD score >20, or of alcoholic hepatitis. hepatic encephalopathy), treatment with prednisolone (which does not require hepatic metabolism, unlike prednisone) is e All patients with advanced alcoholic liver disease should recommended. Contraindications to prednisolone include be referred to hepatology for further management and

vated phosphatidyl ethanol level, and, in advanced cases, ele- assessments and alcohol treatment are required. Alcohol absti- vated INR and thrombocytopenia. The IgA level may be elevated. nence can result in significant stabilization of liver function The Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease and reversal of portal hypertension. Patients with alcoholic Index (www.mayoclinic.org/medical-professionals/model- liver disease and evidence of cirrhosis with or without portal end-stage-liver-disease/alcoholic-liver-disease-nonalcoholic- hypertension should be referred to hepatology for further man- fatty-liver-disease-index) can help distinguish alcoholic liver agement and consideration of liver transplantation, regardless disease from nonalcoholic fatty liver disease. The predictive of duration of alcohol abstinence. Aleohol-induced liver disease model is based on AST, ALT, mean corpuscular volume, age, is the second most common reason for liver transplantation in height, weight, and sex. the United States, behind HCV. Alcoholic hepatitis is most often diagnosed clinically, with liver biopsy reserved for diagnostic uncertainty. Severity of e The Alcoholic Liver Disease/Nonalcoholic Fatty Liver alcoholic hepatitis can be determined by the Maddrey discri- Disease Index can help distinguish alcoholic liver disease minant function (MDF) score, which is calculated as follows: from nonalcoholic fatty liver disease. MDF score = 4.6 (prothrombin time [s] e Manifestations of alcoholic hepatitis include fever. jaundice, - control prothrombin time [s]) tender hepatomegaly, and leukocytosis. + total bilirubin (mg/dL) ® Severity of alcoholic hepatitis is determined by the The Model for End-Stage Liver Disease (MELD) score (https:// Maddrey discriminant function (MDF) score and Modified optn.transplant.hrsa.gov/resources/allocation-calculators/meld- End Stage Liver Disease (MELD) score: patients with an calculator/) can also be used to assess severity, with a MELD MDF score of 32 or greater, MELD score greater than 20, score greater than 20 suggesting moderate to severe disease. or hepatic encephalopathy may be considered for predni- (See Classification of Liver Disease Severity for additional solone therapy. details on components of this score.) e Pentoxifylline is no longer recommended for treatment In severe cases (MDF score 232, MELD score >20, or of alcoholic hepatitis. hepatic encephalopathy), treatment with prednisolone (which does not require hepatic metabolism, unlike prednisone) is e All patients with advanced alcoholic liver disease should recommended. Contraindications to prednisolone include be referred to hepatology for further management and active infection, upper gastrointestinal bleeding, acute kidney consideration of liver transplantation, regardless of

vated phosphatidyl ethanol level, and, in advanced cases, ele- assessments and alcohol treatment are required. Alcohol absti- vated INR and thrombocytopenia. The IgA level may be elevated. nence can result in significant stabilization of liver function The Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease and reversal of portal hypertension. Patients with alcoholic Index (www.mayoclinic.org/medical-professionals/model- liver disease and evidence of cirrhosis with or without portal end-stage-liver-disease/alcoholic-liver-disease-nonalcoholic- hypertension should be referred to hepatology for further man- fatty-liver-disease-index) can help distinguish alcoholic liver agement and consideration of liver transplantation, regardless disease from nonalcoholic fatty liver disease. The predictive of duration of alcohol abstinence. Aleohol-induced liver disease model is based on AST, ALT, mean corpuscular volume, age, is the second most common reason for liver transplantation in height, weight, and sex. the United States, behind HCV. Alcoholic hepatitis is most often diagnosed clinically, with liver biopsy reserved for diagnostic uncertainty. Severity of e The Alcoholic Liver Disease/Nonalcoholic Fatty Liver alcoholic hepatitis can be determined by the Maddrey discri- Disease Index can help distinguish alcoholic liver disease minant function (MDF) score, which is calculated as follows: from nonalcoholic fatty liver disease. MDF score = 4.6 (prothrombin time [s] e Manifestations of alcoholic hepatitis include fever. jaundice, - control prothrombin time [s]) tender hepatomegaly, and leukocytosis. + total bilirubin (mg/dL) ® Severity of alcoholic hepatitis is determined by the The Model for End-Stage Liver Disease (MELD) score (https:// Maddrey discriminant function (MDF) score and Modified optn.transplant.hrsa.gov/resources/allocation-calculators/meld- End Stage Liver Disease (MELD) score: patients with an calculator/) can also be used to assess severity, with a MELD MDF score of 32 or greater, MELD score greater than 20, score greater than 20 suggesting moderate to severe disease. or hepatic encephalopathy may be considered for predni- (See Classification of Liver Disease Severity for additional solone therapy. details on components of this score.) e Pentoxifylline is no longer recommended for treatment In severe cases (MDF score 232, MELD score >20, or of alcoholic hepatitis. hepatic encephalopathy), treatment with prednisolone (which does not require hepatic metabolism, unlike prednisone) is e All patients with advanced alcoholic liver disease should recommended. Contraindications to prednisolone include be referred to hepatology for further management and active infection, upper gastrointestinal bleeding, acute kidney consideration of liver transplantation, regardless of injury, concomitant liver disease (especially HCV and HBV), duration of alcohol abstinence.

recommended. Contraindications to prednisolone include be referred to hepatology for further management and active infection, upper gastrointestinal bleeding, acute kidney consideration of liver transplantation, regardless of injury, concomitant liver disease (especially HCV and HBV), duration of alcohol abstinence. and multiorgan failure. The STOPAH trial showed a trend toward improvement in 28-day mortality with prednisolone, but results were not statistically significant. However, a meta- Drug-Induced Liver Injury analysis of randomized studies (including STOPAH) showed Drug-induced liver injury encompasses a spectrum of liver that glucocorticoids reduced short-term mortality by 46%. injury and can be induced by prescription, over-the-counter, Pentoxifylline is no longer recommended for treatment of and herbal medications. Patients should be asked about expo alcoholic hepatitis and is not effective in patients whose symp- sure to medications in the past 6 months, both prescription toms do not respond to prednisolone. and nonprescription, including supplements. Use of the Response to glucocorticoids can be assessed on day 7 National Institute of Health’s Web-based tool LiverTox (www. with the Lille score (www.mdcale.com/lille-model-alcoholic- livertox.nih.gov) can help assess risk for hepatotoxicity. hepatitis). Because of risk for infection, prednisolone should Acetaminophen is the medication most recognized to be discontinued in patients with no response (Lille score have intrinsic hepatotoxicity. People who chronically drink 20.45). A Lille scores below 0.45 supports prednisolone con- alcohol can develop acetaminophen hepatotoxicity even when tinuation for 28 days. taking therapeutic doses of acetaminophen. The early recogni- Nonsevere alcoholic hepatitis (MDF score <32; MELD tion of acetaminophen-induced liver injury is critical so that score <20) requires supportive measures and should not be N-acetylcysteine can be administered promptly to prevent treated with prednisolone. All patients require assessment liver failure. for nutritional deficiencies, nutritional management, thia- Antibiotics (particularly amoxicillin-clavulanate) and mine replacement, and alcohol treatment, with a goal of antiepileptics (phenytoin and valproate) are also commonly abstinence. associated with drug-induced liver injury, representing 60" of Alcoholic cirrhosis can be diagnosed on clinical and radi- cases. Other than acetaminophen, the drugs most often caus- ologic grounds in patients with obvious evidence of portal ing acute liver failure in the United States are antituberculosis

and multiorgan failure. The STOPAH trial showed a trend toward improvement in 28-day mortality with prednisolone, but results were not statistically significant. However, a meta- Drug-Induced Liver Injury analysis of randomized studies (including STOPAH) showed Drug-induced liver injury encompasses a spectrum of liver that glucocorticoids reduced short-term mortality by 46%. injury and can be induced by prescription, over-the-counter, Pentoxifylline is no longer recommended for treatment of and herbal medications. Patients should be asked about expo alcoholic hepatitis and is not effective in patients whose symp- sure to medications in the past 6 months, both prescription toms do not respond to prednisolone. and nonprescription, including supplements. Use of the Response to glucocorticoids can be assessed on day 7 National Institute of Health’s Web-based tool LiverTox (www. with the Lille score (www.mdcale.com/lille-model-alcoholic- livertox.nih.gov) can help assess risk for hepatotoxicity. hepatitis). Because of risk for infection, prednisolone should Acetaminophen is the medication most recognized to be discontinued in patients with no response (Lille score have intrinsic hepatotoxicity. People who chronically drink 20.45). A Lille scores below 0.45 supports prednisolone con- alcohol can develop acetaminophen hepatotoxicity even when tinuation for 28 days. taking therapeutic doses of acetaminophen. The early recogni- Nonsevere alcoholic hepatitis (MDF score <32; MELD tion of acetaminophen-induced liver injury is critical so that score <20) requires supportive measures and should not be N-acetylcysteine can be administered promptly to prevent treated with prednisolone. All patients require assessment liver failure. for nutritional deficiencies, nutritional management, thia- Antibiotics (particularly amoxicillin-clavulanate) and mine replacement, and alcohol treatment, with a goal of antiepileptics (phenytoin and valproate) are also commonly abstinence. associated with drug-induced liver injury, representing 60" of Alcoholic cirrhosis can be diagnosed on clinical and radi- cases. Other than acetaminophen, the drugs most often caus- ologic grounds in patients with obvious evidence of portal ing acute liver failure in the United States are antituberculosis 59

Disorders of the Liver drugs, sulfa-containing antimicrobial agents, and antifungal Patients with acute liver failure require careful monitor- agents. ing of mental status because progressive hepatic encephalopa- The pattern of liver test abnormalities and histologic thy can result in cerebral edema (see Hepatic Encephalopathy). injury can be unpredictable. In addition to the hepatocellular Kidney injury is common, and continuous renal replacement pattern seen with acetaminophen, a cholestatic pattern (e.g., therapy is better tolerated than intermittent hemodialysis. with amoxicillin-clavulanate) or mixed picture (e.g., with Patients with acute liver failure are at risk for hypoglycemia phenytoin) may be present. Liver injury typically resolves after and infection. discontinuation of the offending drug; resolution of liver Specific treatment is based on the cause, and prompt injury supports the diagnosis. Re-exposure to the drug to treatment is crucial. For example, mortality rates for acetami- demonstrate recurrence is not advisable because of risk for nophen intoxication are lowest when N-acetylcysteine is severe toxicity upon rechallenge. administered within 12 hours of ingestion. Jaundice that occurs with cholestatic drug reactions can take months to resolve. A bilirubin level twice the upper limit e The most common cause of acute liver failure in the of normal with ALT levels greater than three times the upper United States is acetaminophen overdose. limit of normal is associated with mortality rates as high as 14%. Until resolution occurs, progression to liver failure and a ¢ Diagnosis of acute liver failure requires immediate need for liver transplantation are possible. referral to a liver transplant center.

pattern seen with acetaminophen, a cholestatic pattern (e.g., therapy is better tolerated than intermittent hemodialysis. with amoxicillin-clavulanate) or mixed picture (e.g., with Patients with acute liver failure are at risk for hypoglycemia phenytoin) may be present. Liver injury typically resolves after and infection. discontinuation of the offending drug; resolution of liver Specific treatment is based on the cause, and prompt injury supports the diagnosis. Re-exposure to the drug to treatment is crucial. For example, mortality rates for acetami- demonstrate recurrence is not advisable because of risk for nophen intoxication are lowest when N-acetylcysteine is severe toxicity upon rechallenge. administered within 12 hours of ingestion. Jaundice that occurs with cholestatic drug reactions can take months to resolve. A bilirubin level twice the upper limit e The most common cause of acute liver failure in the of normal with ALT levels greater than three times the upper United States is acetaminophen overdose. limit of normal is associated with mortality rates as high as 14%. Until resolution occurs, progression to liver failure and a ¢ Diagnosis of acute liver failure requires immediate need for liver transplantation are possible. referral to a liver transplant center. e Acetaminophen, antibiotics (particularly amoxicillin- Metabolic Liver Diseases clavulanate), and antiepileptics (phenytoin and valproate) Nonalcoholic Fatty Liver Disease are the most common causes of drug-induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is the most common e Liver injury typically resolves after discontinuation of cause of liver disease in the world. Some 30% of the U.S. popu- the offending drug; resolution of liver injury supports lation may have this condition. Most patients with NAFLD do

e Acetaminophen, antibiotics (particularly amoxicillin- Metabolic Liver Diseases clavulanate), and antiepileptics (phenytoin and valproate) Nonalcoholic Fatty Liver Disease are the most common causes of drug-induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is the most common e Liver injury typically resolves after discontinuation of cause of liver disease in the world. Some 30% of the U.S. popu- the offending drug; resolution of liver injury supports lation may have this condition. Most patients with NAFLD do the diagnosis. not have liver inflammation, and fat in the liver without inflammation or fibrosis is considered a relatively benign con- dition. Five percent to 12% of the U.S. population has fatty liver

the diagnosis. not have liver inflammation, and fat in the liver without inflammation or fibrosis is considered a relatively benign con- dition. Five percent to 12% of the U.S. population has fatty liver Acute Liver Failure with inflammation (nonalcoholic steatohepatitis [NASH]) and may have progressive disease that can lead to fibrosis and cir- Acute liver failure is the onset of hepatic encephalopathy and rhosis. Unrecognized NASH is likely a major cause of crypto- prolonged coagulation within 26 weeks of jaundice or other genic cirrhosis. symptoms of liver inflammation in the absence of chronic liver NAFLD is a component of the metabolic syndrome. disease. The most common cause of acute liver failure in the Consequently, the American Diabetes Association recom- United States is acetaminophen overdose. Other widely recog- mends that patients with type 2 diabetes or prediabetes and nized causes are presented in Table 35. Diagnosis requires elevated ALT levels or fatty liver on ultrasonography should be immediate referral to a liver transplant center. evaluated for NASH and liver fibrosis. The mechanisms by

Acute Liver Failure with inflammation (nonalcoholic steatohepatitis [NASH]) and may have progressive disease that can lead to fibrosis and cir- Acute liver failure is the onset of hepatic encephalopathy and rhosis. Unrecognized NASH is likely a major cause of crypto- prolonged coagulation within 26 weeks of jaundice or other genic cirrhosis. symptoms of liver inflammation in the absence of chronic liver NAFLD is a component of the metabolic syndrome. disease. The most common cause of acute liver failure in the Consequently, the American Diabetes Association recom- United States is acetaminophen overdose. Other widely recog- mends that patients with type 2 diabetes or prediabetes and nized causes are presented in Table 35. Diagnosis requires elevated ALT levels or fatty liver on ultrasonography should be immediate referral to a liver transplant center. evaluated for NASH and liver fibrosis. The mechanisms by which patients with NAFLD develop NASH are not fully TABLE 35. Causes of Acute Liver Failure understood, but metabolic, genetic, and environmental factors Acetaminophen | play a role. | Other medications (e.g., antituberculosis drugs, sulfa- NAFLD symptoms are nonspecific and may include | containing antimicrobial agents, antifungal agents, herbal supplements, MDMA) fatigue and vague right-upper-quadrant abdominal pain. Mildly elevated hepatic aminotransferase levels are common Hepatitis A virus in NASH but can be normal even with advanced fibrosis. Hepatitis B virus (with or without hepatitis D virus) NAFLD is often diagnosed by the presence of hepatic fat on Hepatitis E ultrasonography, CT, and MRI. Herpes simplex virus, cytomegalovirus, varicella zoster virus, Besides liver biopsy, no tests can diagnose NASH as a Epstein-Barr virus cause of chronically elevated liver chemistries. Patients with | Autoimmune hepatitis elevated liver chemistries, a negative serologic evaluation for | Wilson disease | alternative causes, clinical features of the metabolic syndrome,

which patients with NAFLD develop NASH are not fully TABLE 35. Causes of Acute Liver Failure understood, but metabolic, genetic, and environmental factors Acetaminophen | play a role. | Other medications (e.g., antituberculosis drugs, sulfa- NAFLD symptoms are nonspecific and may include | containing antimicrobial agents, antifungal agents, herbal supplements, MDMA) fatigue and vague right-upper-quadrant abdominal pain. Mildly elevated hepatic aminotransferase levels are common Hepatitis A virus in NASH but can be normal even with advanced fibrosis. Hepatitis B virus (with or without hepatitis D virus) NAFLD is often diagnosed by the presence of hepatic fat on Hepatitis E ultrasonography, CT, and MRI. Herpes simplex virus, cytomegalovirus, varicella zoster virus, Besides liver biopsy, no tests can diagnose NASH as a Epstein-Barr virus cause of chronically elevated liver chemistries. Patients with | Autoimmune hepatitis elevated liver chemistries, a negative serologic evaluation for | Wilson disease | alternative causes, clinical features of the metabolic syndrome, | Acute hepatic ischemia (e.g., systemic hypotension, Budd- and characteristic abdominal imaging are presumed to have | Chiari Syndrome) NAFLD. High autoantibody titers (antinuclear antibody, anti- | Amanita phalloides mushrooms smooth muscle antibody) are present in 20% of patients with

| Acute hepatic ischemia (e.g., systemic hypotension, Budd- and characteristic abdominal imaging are presumed to have | Chiari Syndrome) NAFLD. High autoantibody titers (antinuclear antibody, anti- | Amanita phalloides mushrooms smooth muscle antibody) are present in 20% of patients with Acute fatty liver of pregnancy NAFLD, but the clinical significance of this is unknown. The NAFLD fibrosis score (www.nafldscore.com) uses clinical MDMA= 3,4-methylenedioxy-inethamphetamine. data to identify patients at risk for severe disease. Transient 60

Disorders of the Liver elastography can help determine whether patients with NASH transferrin saturation and serum ferritin level with HFE geno have developed significant hepatic fibrosis. Liver biopsy is type testing if results of iron studies are abnormal. Children of indicated when the diagnosis is in doubt or the presence of affected patients can be reassured that they do not have hemo- hepatic fibrosis cannot otherwise be determined. chromatosis if the other parent has a normal HFE genotype. NAFLD management focuses on weight loss through diet Hemochromatosis is discussed further in MKSAP 19 and lifestyle modification. No specific diet for NAFLD is rec- Hematology. ommended, although carbohydrate-restricted diets may result in greater reduction in liver fat compared with other diets. Wilson Disease Bariatric surgery and concomitant weight loss exceeding 8% to Wilson disease (hepatolenticular degeneration) is a rare auto 10% improve NAFLD-associated inflammation and fibrosis. No somal recessive disorder that causes copper accumulation in drugs are FDA-approved for primary treatment of NAFLD. the liver. Copper accumulation can result in a range of clinical Cardiovascular disease is the leading cause of death in patients presentations, including asymptomatic liver enzyme abnor with NASH, and statin therapy should be considered, even in malities, cirrhosis, and acute liver failure. Acute liver failure in

elastography can help determine whether patients with NASH transferrin saturation and serum ferritin level with HFE geno have developed significant hepatic fibrosis. Liver biopsy is type testing if results of iron studies are abnormal. Children of indicated when the diagnosis is in doubt or the presence of affected patients can be reassured that they do not have hemo- hepatic fibrosis cannot otherwise be determined. chromatosis if the other parent has a normal HFE genotype. NAFLD management focuses on weight loss through diet Hemochromatosis is discussed further in MKSAP 19 and lifestyle modification. No specific diet for NAFLD is rec- Hematology. ommended, although carbohydrate-restricted diets may result in greater reduction in liver fat compared with other diets. Wilson Disease Bariatric surgery and concomitant weight loss exceeding 8% to Wilson disease (hepatolenticular degeneration) is a rare auto 10% improve NAFLD-associated inflammation and fibrosis. No somal recessive disorder that causes copper accumulation in drugs are FDA-approved for primary treatment of NAFLD. the liver. Copper accumulation can result in a range of clinical Cardiovascular disease is the leading cause of death in patients presentations, including asymptomatic liver enzyme abnor with NASH, and statin therapy should be considered, even in malities, cirrhosis, and acute liver failure. Acute liver failure in the presence of elevated aminotransferase levels. Wilson disease may be accompanied by Coombs-negative hemolytic anemia (secondary to sudden release of copper o,-Antitrypsin Deficiency from hepatocytes) and acute kidney injury. Unexplained liver a, -Antitrypsin deficiency is an autosomal co-dominant genetic disease or liver failure in any patient younger than age disorder that results in accumulation of a variant form of 40 years should prompt an investigation for Wilson disease, o,-antitrypsin in the liver. Homozygosity for this condition may although older patients with Wilson disease have also been cause liver injury and eventual cirrhosis. The hepatic accumula- described. tion of o, antitrypsin also decreases circulating o,-antitrypsin, Neurologic and behavioral changes can be seen in patients leading to lack of inhibition of elastase and resultant lung dis- with Wilson disease (tremor, early-onset Parkinson disease. ease. Patients heterozygous for o,-antitrypsin deficiency are at dystonia). Kayser-Fleischer rings can be seen on slit lamp increased risk for liver injury in the setting of other liver examination in nearly all patients with Wilson disease and diseases, including viral hepatitis and fatty liver disease. neurologic findings and in 50% of patients with liver manifes- Supplemental o,-antitrypsin prevents progressive lung injury tations. Laboratory findings include high levels of urinary but does not affect cirrhosis progression. Liver transplantation copper and low levels of ceruloplasmin and ALP. Histologic is required to treat liver failure resulting from o,-antitrypsin changes on liver biopsy can be nonspecific, although hepatic deficiency. copper levels are typically high. Genetic testing for ATP7B gene mutations confirms Wilson disease. Hereditary Hemochromatosis Treatment is lifelong and involves administration of cop Hereditary hemochromatosis is an autosomal recessive condi- per chelators. Trientine is preferred over penicillamine because tion characterized by excessive accumulation of iron in the of a lower rate of adverse effects. Zinc supplements can be liver due to a mutation in the genes that control hepcidin syn- administered to decrease intestinal absorption of copper. thesis, resulting in increased iron absorption. It typically Urgent liver transplantation is necessary in acute liver failure results from homozygosity of the C282Y polymorphism of the secondary to Wilson disease. HFE gene, but other polymorphisms, such as H63D, can also cause disease. Cirrhosis can develop in untreated patients with hereditary hemochromatosis and is associated with an ® Nonalcoholic fatty liver disease is the most common

the presence of elevated aminotransferase levels. Wilson disease may be accompanied by Coombs-negative hemolytic anemia (secondary to sudden release of copper o,-Antitrypsin Deficiency from hepatocytes) and acute kidney injury. Unexplained liver a, -Antitrypsin deficiency is an autosomal co-dominant genetic disease or liver failure in any patient younger than age disorder that results in accumulation of a variant form of 40 years should prompt an investigation for Wilson disease, o,-antitrypsin in the liver. Homozygosity for this condition may although older patients with Wilson disease have also been cause liver injury and eventual cirrhosis. The hepatic accumula- described. tion of o, antitrypsin also decreases circulating o,-antitrypsin, Neurologic and behavioral changes can be seen in patients leading to lack of inhibition of elastase and resultant lung dis- with Wilson disease (tremor, early-onset Parkinson disease. ease. Patients heterozygous for o,-antitrypsin deficiency are at dystonia). Kayser-Fleischer rings can be seen on slit lamp increased risk for liver injury in the setting of other liver examination in nearly all patients with Wilson disease and diseases, including viral hepatitis and fatty liver disease. neurologic findings and in 50% of patients with liver manifes- Supplemental o,-antitrypsin prevents progressive lung injury tations. Laboratory findings include high levels of urinary but does not affect cirrhosis progression. Liver transplantation copper and low levels of ceruloplasmin and ALP. Histologic is required to treat liver failure resulting from o,-antitrypsin changes on liver biopsy can be nonspecific, although hepatic deficiency. copper levels are typically high. Genetic testing for ATP7B gene mutations confirms Wilson disease. Hereditary Hemochromatosis Treatment is lifelong and involves administration of cop Hereditary hemochromatosis is an autosomal recessive condi- per chelators. Trientine is preferred over penicillamine because tion characterized by excessive accumulation of iron in the of a lower rate of adverse effects. Zinc supplements can be liver due to a mutation in the genes that control hepcidin syn- administered to decrease intestinal absorption of copper. thesis, resulting in increased iron absorption. It typically Urgent liver transplantation is necessary in acute liver failure results from homozygosity of the C282Y polymorphism of the secondary to Wilson disease. HFE gene, but other polymorphisms, such as H63D, can also cause disease. Cirrhosis can develop in untreated patients with hereditary hemochromatosis and is associated with an ® Nonalcoholic fatty liver disease is the most common increased risk for hepatocellular carcinoma. cause of liver disease in the world, and management is

the presence of elevated aminotransferase levels. Wilson disease may be accompanied by Coombs-negative hemolytic anemia (secondary to sudden release of copper o,-Antitrypsin Deficiency from hepatocytes) and acute kidney injury. Unexplained liver a, -Antitrypsin deficiency is an autosomal co-dominant genetic disease or liver failure in any patient younger than age disorder that results in accumulation of a variant form of 40 years should prompt an investigation for Wilson disease, o,-antitrypsin in the liver. Homozygosity for this condition may although older patients with Wilson disease have also been cause liver injury and eventual cirrhosis. The hepatic accumula- described. tion of o, antitrypsin also decreases circulating o,-antitrypsin, Neurologic and behavioral changes can be seen in patients leading to lack of inhibition of elastase and resultant lung dis- with Wilson disease (tremor, early-onset Parkinson disease. ease. Patients heterozygous for o,-antitrypsin deficiency are at dystonia). Kayser-Fleischer rings can be seen on slit lamp increased risk for liver injury in the setting of other liver examination in nearly all patients with Wilson disease and diseases, including viral hepatitis and fatty liver disease. neurologic findings and in 50% of patients with liver manifes- Supplemental o,-antitrypsin prevents progressive lung injury tations. Laboratory findings include high levels of urinary but does not affect cirrhosis progression. Liver transplantation copper and low levels of ceruloplasmin and ALP. Histologic is required to treat liver failure resulting from o,-antitrypsin changes on liver biopsy can be nonspecific, although hepatic deficiency. copper levels are typically high. Genetic testing for ATP7B gene mutations confirms Wilson disease. Hereditary Hemochromatosis Treatment is lifelong and involves administration of cop Hereditary hemochromatosis is an autosomal recessive condi- per chelators. Trientine is preferred over penicillamine because tion characterized by excessive accumulation of iron in the of a lower rate of adverse effects. Zinc supplements can be liver due to a mutation in the genes that control hepcidin syn- administered to decrease intestinal absorption of copper. thesis, resulting in increased iron absorption. It typically Urgent liver transplantation is necessary in acute liver failure results from homozygosity of the C282Y polymorphism of the secondary to Wilson disease. HFE gene, but other polymorphisms, such as H63D, can also cause disease. Cirrhosis can develop in untreated patients with hereditary hemochromatosis and is associated with an ® Nonalcoholic fatty liver disease is the most common increased risk for hepatocellular carcinoma. cause of liver disease in the world, and management is Elevated transferrin saturation and elevated serum ferri- focused on weight loss through dietary and lifestyle

the presence of elevated aminotransferase levels. Wilson disease may be accompanied by Coombs-negative hemolytic anemia (secondary to sudden release of copper o,-Antitrypsin Deficiency from hepatocytes) and acute kidney injury. Unexplained liver a, -Antitrypsin deficiency is an autosomal co-dominant genetic disease or liver failure in any patient younger than age disorder that results in accumulation of a variant form of 40 years should prompt an investigation for Wilson disease, o,-antitrypsin in the liver. Homozygosity for this condition may although older patients with Wilson disease have also been cause liver injury and eventual cirrhosis. The hepatic accumula- described. tion of o, antitrypsin also decreases circulating o,-antitrypsin, Neurologic and behavioral changes can be seen in patients leading to lack of inhibition of elastase and resultant lung dis- with Wilson disease (tremor, early-onset Parkinson disease. ease. Patients heterozygous for o,-antitrypsin deficiency are at dystonia). Kayser-Fleischer rings can be seen on slit lamp increased risk for liver injury in the setting of other liver examination in nearly all patients with Wilson disease and diseases, including viral hepatitis and fatty liver disease. neurologic findings and in 50% of patients with liver manifes- Supplemental o,-antitrypsin prevents progressive lung injury tations. Laboratory findings include high levels of urinary but does not affect cirrhosis progression. Liver transplantation copper and low levels of ceruloplasmin and ALP. Histologic is required to treat liver failure resulting from o,-antitrypsin changes on liver biopsy can be nonspecific, although hepatic deficiency. copper levels are typically high. Genetic testing for ATP7B gene mutations confirms Wilson disease. Hereditary Hemochromatosis Treatment is lifelong and involves administration of cop Hereditary hemochromatosis is an autosomal recessive condi- per chelators. Trientine is preferred over penicillamine because tion characterized by excessive accumulation of iron in the of a lower rate of adverse effects. Zinc supplements can be liver due to a mutation in the genes that control hepcidin syn- administered to decrease intestinal absorption of copper. thesis, resulting in increased iron absorption. It typically Urgent liver transplantation is necessary in acute liver failure results from homozygosity of the C282Y polymorphism of the secondary to Wilson disease. HFE gene, but other polymorphisms, such as H63D, can also cause disease. Cirrhosis can develop in untreated patients with hereditary hemochromatosis and is associated with an ® Nonalcoholic fatty liver disease is the most common increased risk for hepatocellular carcinoma. cause of liver disease in the world, and management is Elevated transferrin saturation and elevated serum ferri- focused on weight loss through dietary and lifestyle tin levels suggest hereditary hemochromatosis, but genetic modification.

increased risk for hepatocellular carcinoma. cause of liver disease in the world, and management is Elevated transferrin saturation and elevated serum ferri- focused on weight loss through dietary and lifestyle tin levels suggest hereditary hemochromatosis, but genetic modification. testing is required to confirm the diagnosis. ¢ o,-Antitrypsin deficiency is an autosomal co-dominant Cirrhosis should be suspected in all patients with heredi- genetic disorder that results in accumulation of a variant tary hemochromatosis who have a serum ferritin level greater protein in the liver; homozygosity can result in liver injury than 1000 ng/mL (1000 pg/L) or those with physical examina- and cirrhosis. tion or imaging findings suggesting cirrhosis. Removal of e Hereditary hemochromatosis is characterized by excessive excessive iron, usually by phlebotomy, prevents cirrhosis. iron absorption that results in accumulation of iron in Patients with cirrhosis should undergo iron-lowering therapy the liver and cirrhosis. to stabilize liver disease and prevent other organ manifesta- e Wilson disease is a rare autosomal recessive disorder tions of iron overload; they should also be screened for that causes accumulation of copper in the liver; it can hepatocellular carcinoma. Liver failure from hereditary hemo- present in young patients (<40 years) with acute liver chromatosis is treated by liver transplantation. failure accompanied by Coombs-negative hemolytic First-degree relatives of patients with hereditary hemo- anemia and acute kidney injury. chromatosis should be screened with iron studies, including 61

Disorders of the Liver FIGURE 33. Endoscopic images of large esophageal varices with red wale marks FIGURE 34. Endoscopic view of diffuse gastric antral vascular ectasias in the characterized by erythematous raised areas (arrows). These varices are at risk for setting of portal hypertension. spontaneous hemorrhage and are an indication for prophylactic therapy. If pressure in the lumen of a varix increases, esophageal eradicate gastric varices via the systemic circulation. Isolated varices enlarge and may spontaneously rupture, leading to gastric varices can occur with splenic vein thrombosis and are bleeding, which may be massive. Treatment can reduce the treated with splenectomy. risk for acute variceal hemorrhage and associated mortality. Portal hypertensive gastropathy is the presence of dilated Upper endoscopy should be performed in all patients with cir- mucosal gastric veins and venules and is a common endo- rhosis to assess for varices. Management of varices in patients scopic finding in patients with cirrhosis. It is rarely a cause of with cirrhosis depends on varix size and whether cirrhosis is significant acute bleeding but may cause chronic blood loss.

If pressure in the lumen of a varix increases, esophageal eradicate gastric varices via the systemic circulation. Isolated varices enlarge and may spontaneously rupture, leading to gastric varices can occur with splenic vein thrombosis and are bleeding, which may be massive. Treatment can reduce the treated with splenectomy. risk for acute variceal hemorrhage and associated mortality. Portal hypertensive gastropathy is the presence of dilated Upper endoscopy should be performed in all patients with cir- mucosal gastric veins and venules and is a common endo- rhosis to assess for varices. Management of varices in patients scopic finding in patients with cirrhosis. It is rarely a cause of with cirrhosis depends on varix size and whether cirrhosis is significant acute bleeding but may cause chronic blood loss. compensated (Table 37). Treatment is centered on the underlying portal hypertension. See Gastrointestinal Bleeding for discussion of manage- Gastric antral vascular ectasias consist of ectatic vessels ment and secondary prophylaxis of variceal hemorrhage. that line the mucosa of the distal stomach. These can be pre- sent in patients without cirrhosis, but in the setting of portal Gastric Varices and Portal hypertension, these mucosal lesions tend to be more diffuse Hypertensive Gastropathy (Figure 34) than the classic linear pattern (“watermelon stom- Gastric varices are seen in up to 20% of patients with cirrhosis ach”). These are typically treated with endoscopic therapy, and are responsible for 10% to 30% of variceal hemorrhages. such as argon plasma coagulation. Portal decompressive inter-

compensated (Table 37). Treatment is centered on the underlying portal hypertension. See Gastrointestinal Bleeding for discussion of manage- Gastric antral vascular ectasias consist of ectatic vessels ment and secondary prophylaxis of variceal hemorrhage. that line the mucosa of the distal stomach. These can be pre- sent in patients without cirrhosis, but in the setting of portal Gastric Varices and Portal hypertension, these mucosal lesions tend to be more diffuse Hypertensive Gastropathy (Figure 34) than the classic linear pattern (“watermelon stom- Gastric varices are seen in up to 20% of patients with cirrhosis ach”). These are typically treated with endoscopic therapy, and are responsible for 10% to 30% of variceal hemorrhages. such as argon plasma coagulation. Portal decompressive inter- Varices that extend from the esophagus into the cardia of the ventions such as TIPS do not effectively treat gastric antral stomach, along the lesser curvature of the stomach, are treated vascular ectasias.

compensated (Table 37). Treatment is centered on the underlying portal hypertension. See Gastrointestinal Bleeding for discussion of manage- Gastric antral vascular ectasias consist of ectatic vessels ment and secondary prophylaxis of variceal hemorrhage. that line the mucosa of the distal stomach. These can be pre- sent in patients without cirrhosis, but in the setting of portal Gastric Varices and Portal hypertension, these mucosal lesions tend to be more diffuse Hypertensive Gastropathy (Figure 34) than the classic linear pattern (“watermelon stom- Gastric varices are seen in up to 20% of patients with cirrhosis ach”). These are typically treated with endoscopic therapy, and are responsible for 10% to 30% of variceal hemorrhages. such as argon plasma coagulation. Portal decompressive inter- Varices that extend from the esophagus into the cardia of the ventions such as TIPS do not effectively treat gastric antral stomach, along the lesser curvature of the stomach, are treated vascular ectasias. with band ligation, similar to esophageal varices. Varices of the gastric fundus or isolated varices in other parts of the stomach Ascites are generally not amenable to band ligation. Bleeding varices Ascites occurs in 50% of patients within 10 years of cirrhosis in these areas are treated with hemodynamic resuscitation, diagnosis and is the most common symptom of decompen- antibiotic therapy, and octreotide. A transjugular intrahepatic sated cirrhosis. Physical examination maneuvers can detect portosystemic shunt (TIPS) can be considered for bleeding ascites, although they perform poorly compared with ultra- from gastric varices. Balloon-occluded retrograde transvenous sonography, which has high sensitivity for identifying ascites. obliteration is another interventional radiologic procedure to When ascites is first detected, diagnostic paracentesis should

with band ligation, similar to esophageal varices. Varices of the gastric fundus or isolated varices in other parts of the stomach Ascites are generally not amenable to band ligation. Bleeding varices Ascites occurs in 50% of patients within 10 years of cirrhosis in these areas are treated with hemodynamic resuscitation, diagnosis and is the most common symptom of decompen- antibiotic therapy, and octreotide. A transjugular intrahepatic sated cirrhosis. Physical examination maneuvers can detect portosystemic shunt (TIPS) can be considered for bleeding ascites, although they perform poorly compared with ultra- from gastric varices. Balloon-occluded retrograde transvenous sonography, which has high sensitivity for identifying ascites. obliteration is another interventional radiologic procedure to When ascites is first detected, diagnostic paracentesis should TABLE 37. Management of Screening-Detected Esophageal Varices in Patients With Compensated Cirrhosis Findings Management No varices Repeat upper endoscopy in 3 years (unless decompensation occurs) Small varices (<5 mm) Repeat upper endoscopy in 2 years (unless decompensation occurs) Small varices with red wale marks (erythematous raised areas) _ Initiate nonselective B-blocker therapy (propranolol, nadolol, or carvedilol) Large varices (+5 mm) Initiate nonselective B-blocker therapy or endoscopic variceal ligation Varices in patients unable to tolerate B-blockers Endoscopic variceal ligation 64

Disorders of the Liver TABLE 38. Characteristics of Ascites Ascitic Fluid Total Other Characteristics | Protein Level Cirrhosis High? Low Clear, straw-colored _ | High triglycerides | | Heart failure High? High* | Chylous ascites Low? or high? — High* SAAG can be high if caused by portal hypertension | SAAG is low if caused by lymphatic disruption | Tuberculosis Low? Highs Peritoneal biopsy may be required to confirm diagnosis of tuberculosis | Malignancy Low? High¢ Positive cytology results | Nephrotic syndrome — Low? Low? Proteinuria and edema SAAG = serum-ascites albumin gradient. 921.1 g/dL (11 g/L). 52.5 g/dL (25 g/L). 2.5 g/dL.(25 g/L). 9<1.1 g/dL (11 g/L).

Tuberculosis Low? Highs Peritoneal biopsy may be required to confirm diagnosis of tuberculosis | Malignancy Low? High¢ Positive cytology results | Nephrotic syndrome — Low? Low? Proteinuria and edema SAAG = serum-ascites albumin gradient. 921.1 g/dL (11 g/L). 52.5 g/dL (25 g/L). 2.5 g/dL.(25 g/L). 9<1.1 g/dL (11 g/L). be performed. The serum-ascites albumin gradient is meas- Indwelling chest tubes are not helpful and should be avoided ured by subtracting the level of albumin in the ascitic fluid because of the high risk for complications. from the serum albumin measurement: Spontaneous Bacterial Peritonitis serum —ascites albumin gradient = serum albumin Spontaneous bacterial peritonitis (SBP) is an infection of por- — ascites albumin tal hypertensive ascitic fluids. SBP can present with fever, Total protein levels in ascitic fluid also help determine abdominal pain, and/or kidney dysfunction; it should be con- cause of the ascites. The characteristics of ascites are presented sidered in any patient with ascites whose clinical status in Table 38. declines. In patients with cirrhosis and ascites, long-term In 85% of patients with ascites, the cause is cirrhosis. prophylactic antibiotic therapy, typically with a fluoroqui- Management of ascites involves a sodium-restricted diet nolone, is recommended to prevent SBP if the ascitic fluid (<2 g/d). Diuretic therapy, typically with spironolactone and protein level is less than 1.5 g/dL (15 g/L) and is associated furosemide, is often required to assist natriuresis. Kidney with impaired renal function (serum creatinine 21.2 mg/dL function and electrolyte levels are checked 7 to 10 days after [106.1 umol/L], blood urea nitrogen >25 mg/dL [8.9 mmol/L], changes to diuretic regimens. or serum sodium <130 mEq/L [130 mmol/L]) or liver failtire Paracenteses can be performed if ascites does not resolve (CTP score >9 and bilirubin level >3 mg/dL [51.3 umol/L]). with sodium restriction and diuretic therapy or if diuretic SBP is diagnosed by an ascitic-fluid neutrophil count of therapy is poorly tolerated. If more than 5 L of ascitic fluid is 250/uL (0.25 x 109/L) or higher on diagnostic paracentesis. removed at one time, supplemental 25% albumin at a dose of 6 Bacterial culture of ascitic fluid, obtained after direct inocula- to 8 g/L of ascitic fluid removed should be administered to tion of fluid into culture bottles, should also be performed but prevent circulatory dysfunction after paracentesis. is often negative. Prompt initiation of a third-generation ceph- Patients with ascites should discontinue ACE inhibitors alosporin is the initial treatment of SBP. Patients with kidney and NSAIDs. Intermittent paracentesis or TIPS can be consid- dysfunction or significant hepatic dysfunction (defined as ered in patients with refractory ascites and a low MELD score. serum bilirubin level >4 mg/dL [68 umol/L]) should receive Indwelling drains in ascites due to portal hypertension are not adjunctive albumin therapy (1.5 g/kg body weight on day 1 and recommended because of high rates of complications, 1 g/kg on day 3); such treatment has a survival benefit. although they may be considered for end-of-life palliation. Follow-up paracentesis to demonstrate lessened inflamma- Patients with ascites can develop pleural effusions tion can be performed if clinical improvement is not obvious. (hepatic hydrothorax) because of permeability of the dia- SBP commonly recurs, and indefinite secondary prophylactic phragm and negative intrathoracic pressure. These effusions therapy should be offered after SBP resolves, typically with once- tend to be right-sided. Exclusion of other causes of pleural daily fluoroquinolone therapy. Discontinuing nonselective effusions is necessary. Management is similar to that for B-blocker therapy, if present, should be considered because of ascites, with dietary sodium restriction and diuretic therapy. the potential for increased mortality in patients with SBP. SBP Symptomatic hepatic hydrothorax may require thoracentesis has a high mortality rate, and patients who develop SBP should or TIPS. Chemical pleurodesis is typically not beneficial. be considered for liver transplantation.

be performed. The serum-ascites albumin gradient is meas- Indwelling chest tubes are not helpful and should be avoided ured by subtracting the level of albumin in the ascitic fluid because of the high risk for complications. from the serum albumin measurement: Spontaneous Bacterial Peritonitis serum —ascites albumin gradient = serum albumin Spontaneous bacterial peritonitis (SBP) is an infection of por- — ascites albumin tal hypertensive ascitic fluids. SBP can present with fever, Total protein levels in ascitic fluid also help determine abdominal pain, and/or kidney dysfunction; it should be con- cause of the ascites. The characteristics of ascites are presented sidered in any patient with ascites whose clinical status in Table 38. declines. In patients with cirrhosis and ascites, long-term In 85% of patients with ascites, the cause is cirrhosis. prophylactic antibiotic therapy, typically with a fluoroqui- Management of ascites involves a sodium-restricted diet nolone, is recommended to prevent SBP if the ascitic fluid (<2 g/d). Diuretic therapy, typically with spironolactone and protein level is less than 1.5 g/dL (15 g/L) and is associated furosemide, is often required to assist natriuresis. Kidney with impaired renal function (serum creatinine 21.2 mg/dL function and electrolyte levels are checked 7 to 10 days after [106.1 umol/L], blood urea nitrogen >25 mg/dL [8.9 mmol/L], changes to diuretic regimens. or serum sodium <130 mEq/L [130 mmol/L]) or liver failtire Paracenteses can be performed if ascites does not resolve (CTP score >9 and bilirubin level >3 mg/dL [51.3 umol/L]). with sodium restriction and diuretic therapy or if diuretic SBP is diagnosed by an ascitic-fluid neutrophil count of therapy is poorly tolerated. If more than 5 L of ascitic fluid is 250/uL (0.25 x 109/L) or higher on diagnostic paracentesis. removed at one time, supplemental 25% albumin at a dose of 6 Bacterial culture of ascitic fluid, obtained after direct inocula- to 8 g/L of ascitic fluid removed should be administered to tion of fluid into culture bottles, should also be performed but prevent circulatory dysfunction after paracentesis. is often negative. Prompt initiation of a third-generation ceph- Patients with ascites should discontinue ACE inhibitors alosporin is the initial treatment of SBP. Patients with kidney and NSAIDs. Intermittent paracentesis or TIPS can be consid- dysfunction or significant hepatic dysfunction (defined as ered in patients with refractory ascites and a low MELD score. serum bilirubin level >4 mg/dL [68 umol/L]) should receive Indwelling drains in ascites due to portal hypertension are not adjunctive albumin therapy (1.5 g/kg body weight on day 1 and recommended because of high rates of complications, 1 g/kg on day 3); such treatment has a survival benefit. although they may be considered for end-of-life palliation. Follow-up paracentesis to demonstrate lessened inflamma- Patients with ascites can develop pleural effusions tion can be performed if clinical improvement is not obvious. (hepatic hydrothorax) because of permeability of the dia- SBP commonly recurs, and indefinite secondary prophylactic phragm and negative intrathoracic pressure. These effusions therapy should be offered after SBP resolves, typically with once- tend to be right-sided. Exclusion of other causes of pleural daily fluoroquinolone therapy. Discontinuing nonselective effusions is necessary. Management is similar to that for B-blocker therapy, if present, should be considered because of ascites, with dietary sodium restriction and diuretic therapy. the potential for increased mortality in patients with SBP. SBP Symptomatic hepatic hydrothorax may require thoracentesis has a high mortality rate, and patients who develop SBP should or TIPS. Chemical pleurodesis is typically not beneficial. be considered for liver transplantation. 65

Disorders of the Liver TABLE 39. Classification of Hepatic Encephalopathy | Severity of Description Findings Encephalopathy | Minimal Detected only on neuropsychiatric testing Few or absent clinical manifestations | Grade 1 Mild lack of awareness, sleep disturbances Oriented to time and place, but with psychomotor slowing | Grade 2 Lethargic, disoriented, and with personality change Disoriented to time, with asterixis Grade 3 Somnolence, confusion, and significant disorientation — Disoriented to time, place, and situation, with asterixis Grade 4 Coma Lack of response even to painful stimuli Adapted with permission from Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60:715-35. [PMID: 25042402] doi:10.1002/hep.27210. © 2014 by the American Association for the Study of Liver Diseases. Hepatic Encephalopathy acute kidney injury (especially volume depletion). Patients Hepatic encephalopathy (HE) is brain dysfunction ranging have low fractional excretion of sodium and oliguria. Type 2 from minimal abnormalities to frank coma. It results from HRS is characterized by a gradual decline in kidney function insufficient hepatic function and portasystemic shunting of associated with refractory ascites. blood caused by portal hypertension. HE can develop sponta- Declining renal function is one of the most important neously or be precipitated by other factors, such as infection, predictors of death in patients with cirrhosis. A rapid rise of sedating medications, volume depletion, or gastrointestinal serum creatinine should prompt evaluation for infections and

blood caused by portal hypertension. HE can develop sponta- Declining renal function is one of the most important neously or be precipitated by other factors, such as infection, predictors of death in patients with cirrhosis. A rapid rise of sedating medications, volume depletion, or gastrointestinal serum creatinine should prompt evaluation for infections and bleeding, and it heralds worsening liver function. causes of hypovolemia. Detection of minimal HE manifestations requires neu- Management of HRS involves treatment of precipitating ropsychiatric testing, although overt changes of HE, ranging conditions, withdrawal of diuretics, and volume expansion from personality changes to frank coma, are common in with intravenous albumin. Vasoconstrictor treatment with advanced cirrhosis (Table 39). Asterixis—a flapping hand midodrine and octreotide or norepinephrine to raise mean tremor-—is typically present in middle stages of hepatic enceph- arterial pressure and improve renal perfusion may be useful. alopathy. Asterixis is absent in subclinical hepatic encepha- Treatment may also include intravenous albumin with either lopathy and is lost as patients progress to later stages of hepatic terlipressin (if available) or midodrine and octreotide to raise encephalopathy, including coma. mean arterial pressure and improve kidney perfusion. Patients Patients with severe hepatic encephalopathy should be whose kidney function does not improve with therapy may monitored in an ICU. Diminishing consciousness should require hemodialysis while they await liver transplantation.

lopathy and is lost as patients progress to later stages of hepatic terlipressin (if available) or midodrine and octreotide to raise encephalopathy, including coma. mean arterial pressure and improve kidney perfusion. Patients Patients with severe hepatic encephalopathy should be whose kidney function does not improve with therapy may monitored in an ICU. Diminishing consciousness should require hemodialysis while they await liver transplantation. prompt consideration of intubation if airway-protective reflexes are lost. Hepatopulmonary Syndrome Treatment of hepatic encephalopathy is multifaceted. Hepatopulmonary syndrome (HPS) is characterized by dila Precipitating causes, such as infection or gastrointestinal tion of intrapulmonary vessels in patients with portal hyper- bleeding. should be promptly treated, and sedating medi- tension, resulting in right-to-left shunting of blood and cations should be discontinued. Administration of the hypoxemia. The dilated vessels reside in the inferior aspects of nonabsorbed disaccharide lactulose decreases absorption of the lungs, and increased perfusion of these areas in the upright nitrogenous substances and results in improvement in most position results in orthodeoxia (worsening oxygen saturation patients. If response to lactulose therapy is suboptimal, rifaxi- while upright) and platypnea (worsening dyspnea when min can be given to alter bacterial flora in the intestine. upright). The diagnosis should be suspected in patients with Although rifaximin is better tolerated than lactulose, it is often portal hypertension who have dyspnea and hypoxemia. not first-line therapy because of its expense. Findings of intrapulmonary shunting upon agitated saline administration during echocardiography confirm the diagno- Hepatorenal Syndrome sis. Macroaggregated albumin perfusion studies can also aid in

prompt consideration of intubation if airway-protective reflexes are lost. Hepatopulmonary Syndrome Treatment of hepatic encephalopathy is multifaceted. Hepatopulmonary syndrome (HPS) is characterized by dila Precipitating causes, such as infection or gastrointestinal tion of intrapulmonary vessels in patients with portal hyper- bleeding. should be promptly treated, and sedating medi- tension, resulting in right-to-left shunting of blood and cations should be discontinued. Administration of the hypoxemia. The dilated vessels reside in the inferior aspects of nonabsorbed disaccharide lactulose decreases absorption of the lungs, and increased perfusion of these areas in the upright nitrogenous substances and results in improvement in most position results in orthodeoxia (worsening oxygen saturation patients. If response to lactulose therapy is suboptimal, rifaxi- while upright) and platypnea (worsening dyspnea when min can be given to alter bacterial flora in the intestine. upright). The diagnosis should be suspected in patients with Although rifaximin is better tolerated than lactulose, it is often portal hypertension who have dyspnea and hypoxemia. not first-line therapy because of its expense. Findings of intrapulmonary shunting upon agitated saline administration during echocardiography confirm the diagno- Hepatorenal Syndrome sis. Macroaggregated albumin perfusion studies can also aid in Hepatorenal syndrome (HRS) occurs in the setting of portal diagnosis. HPS is initially treated with supplemental oxygen,

prompt consideration of intubation if airway-protective reflexes are lost. Hepatopulmonary Syndrome Treatment of hepatic encephalopathy is multifaceted. Hepatopulmonary syndrome (HPS) is characterized by dila Precipitating causes, such as infection or gastrointestinal tion of intrapulmonary vessels in patients with portal hyper- bleeding. should be promptly treated, and sedating medi- tension, resulting in right-to-left shunting of blood and cations should be discontinued. Administration of the hypoxemia. The dilated vessels reside in the inferior aspects of nonabsorbed disaccharide lactulose decreases absorption of the lungs, and increased perfusion of these areas in the upright nitrogenous substances and results in improvement in most position results in orthodeoxia (worsening oxygen saturation patients. If response to lactulose therapy is suboptimal, rifaxi- while upright) and platypnea (worsening dyspnea when min can be given to alter bacterial flora in the intestine. upright). The diagnosis should be suspected in patients with Although rifaximin is better tolerated than lactulose, it is often portal hypertension who have dyspnea and hypoxemia. not first-line therapy because of its expense. Findings of intrapulmonary shunting upon agitated saline administration during echocardiography confirm the diagno- Hepatorenal Syndrome sis. Macroaggregated albumin perfusion studies can also aid in Hepatorenal syndrome (HRS) occurs in the setting of portal diagnosis. HPS is initially treated with supplemental oxygen, hypertension and is due to reduced renal blood flow during but the only effective treatment is liver transplantation. simultaneous dilatation of the splanchnic vasculature. Most patients who develop HRS have cirrhosis, although alcoholic Portopulmonary Hypertension hepatitis and acute liver failure are also associated with HRS. Portopulmonary hypertension should be suspected in patients Type 1 HRS is characterized by a rise in serum creatinine of at with cirrhosis and portal hypertension who present with least 0.3 mg/dL (26.5 umol/L) and/or 50% or greater from dyspnea on exertion. Although less common than HPS, baseline within 48 hours, bland urinalysis, normal kidney portopulmonary hypertension is a complication of advanced ultrasonography findings, and exclusion of other causes of cirrhosis with a high mortality rate. Echocardiography

hypertension and is due to reduced renal blood flow during but the only effective treatment is liver transplantation. simultaneous dilatation of the splanchnic vasculature. Most patients who develop HRS have cirrhosis, although alcoholic Portopulmonary Hypertension hepatitis and acute liver failure are also associated with HRS. Portopulmonary hypertension should be suspected in patients Type 1 HRS is characterized by a rise in serum creatinine of at with cirrhosis and portal hypertension who present with least 0.3 mg/dL (26.5 umol/L) and/or 50% or greater from dyspnea on exertion. Although less common than HPS, baseline within 48 hours, bland urinalysis, normal kidney portopulmonary hypertension is a complication of advanced ultrasonography findings, and exclusion of other causes of cirrhosis with a high mortality rate. Echocardiography 66

Disorders of the Liver demonstrates right ventricular systolic pressures greater than benzodiazepines, should be avoided to prevent hepatic 50 mm Hg, which necessitates right-heart catheterization to encephalopathy. Patients should avoid consuming raw shell- confirm the diagnosis. Although portopulmonary hyperten- fish, which can transmit Vibrio vulnificus, an organism caus- sion was formerly a contraindication to liver transplantation, ing potentially fatal infection in patients with cirrhosis. patients with preserved right ventricular function who attain Metabolic bone disease is common in patients with cir- a mean pulmonary artery pressure less than 35 mm Hg with rhosis, and patients should be screened for osteoporosis. The vasodilator therapies can benefit from liver transplantation. development of osteoporosis in patients with cirrhosis is Prostacyclin analogues, phosphodiesterase inhibitors, and multifactorial and is associated with jaundice (negatively endothelin receptor antagonists have been used to treat por- affects osteoblast viability), hypogonadism, and decreased topulmonary hypertension. levels of insulin-like growth factor. Cholestasis also decreases absorption of vitamin D. Patients with osteoporosis are treated with calcium supplementation and antiresorptive e Upper endoscopy should be performed in patients with agents. Patients with esophageal varices should receive intra- cirrhosis to assess for esophageal varices; primary venous rather than oral bisphosphonates. Patients with prophylaxis to prevent bleeding includes nonselective osteopenia should be treated with supplemental calcium plus 6-blocker therapy (propranolol, nadolol, or carvedilol) vitamin D. Weight-bearing exercises are encouraged in or endoscopic variceal ligation. patients with cirrhosis. e Precipitating causes of hepatic encephalopathy may Protein-calorie malnutrition is common in patients with include infection, sedating medications, volume deple- cirrhosis. Protein consumption is essential to prevent the cata- tion, or gastrointestinal bleeding; treatment involves bolic effects of chronic liver disease. Patients with cirrhosis addressing the precipitating cause and administering should consume 1.5 g of protein/d per kg of body weight. lactulose or rifaximin. Medications metabolized by the liver may require dosage

demonstrates right ventricular systolic pressures greater than benzodiazepines, should be avoided to prevent hepatic 50 mm Hg, which necessitates right-heart catheterization to encephalopathy. Patients should avoid consuming raw shell- confirm the diagnosis. Although portopulmonary hyperten- fish, which can transmit Vibrio vulnificus, an organism caus- sion was formerly a contraindication to liver transplantation, ing potentially fatal infection in patients with cirrhosis. patients with preserved right ventricular function who attain Metabolic bone disease is common in patients with cir- a mean pulmonary artery pressure less than 35 mm Hg with rhosis, and patients should be screened for osteoporosis. The vasodilator therapies can benefit from liver transplantation. development of osteoporosis in patients with cirrhosis is Prostacyclin analogues, phosphodiesterase inhibitors, and multifactorial and is associated with jaundice (negatively endothelin receptor antagonists have been used to treat por- affects osteoblast viability), hypogonadism, and decreased topulmonary hypertension. levels of insulin-like growth factor. Cholestasis also decreases absorption of vitamin D. Patients with osteoporosis are treated with calcium supplementation and antiresorptive e Upper endoscopy should be performed in patients with agents. Patients with esophageal varices should receive intra- cirrhosis to assess for esophageal varices; primary venous rather than oral bisphosphonates. Patients with prophylaxis to prevent bleeding includes nonselective osteopenia should be treated with supplemental calcium plus 6-blocker therapy (propranolol, nadolol, or carvedilol) vitamin D. Weight-bearing exercises are encouraged in or endoscopic variceal ligation. patients with cirrhosis. e Precipitating causes of hepatic encephalopathy may Protein-calorie malnutrition is common in patients with include infection, sedating medications, volume deple- cirrhosis. Protein consumption is essential to prevent the cata- tion, or gastrointestinal bleeding; treatment involves bolic effects of chronic liver disease. Patients with cirrhosis addressing the precipitating cause and administering should consume 1.5 g of protein/d per kg of body weight. lactulose or rifaximin. Medications metabolized by the liver may require dosage HVC e Ultrasonography is the most effective means of identify- adjustments depending on cirrhosis severity. Patients with

demonstrates right ventricular systolic pressures greater than benzodiazepines, should be avoided to prevent hepatic 50 mm Hg, which necessitates right-heart catheterization to encephalopathy. Patients should avoid consuming raw shell- confirm the diagnosis. Although portopulmonary hyperten- fish, which can transmit Vibrio vulnificus, an organism caus- sion was formerly a contraindication to liver transplantation, ing potentially fatal infection in patients with cirrhosis. patients with preserved right ventricular function who attain Metabolic bone disease is common in patients with cir- a mean pulmonary artery pressure less than 35 mm Hg with rhosis, and patients should be screened for osteoporosis. The vasodilator therapies can benefit from liver transplantation. development of osteoporosis in patients with cirrhosis is Prostacyclin analogues, phosphodiesterase inhibitors, and multifactorial and is associated with jaundice (negatively endothelin receptor antagonists have been used to treat por- affects osteoblast viability), hypogonadism, and decreased topulmonary hypertension. levels of insulin-like growth factor. Cholestasis also decreases absorption of vitamin D. Patients with osteoporosis are treated with calcium supplementation and antiresorptive e Upper endoscopy should be performed in patients with agents. Patients with esophageal varices should receive intra- cirrhosis to assess for esophageal varices; primary venous rather than oral bisphosphonates. Patients with prophylaxis to prevent bleeding includes nonselective osteopenia should be treated with supplemental calcium plus 6-blocker therapy (propranolol, nadolol, or carvedilol) vitamin D. Weight-bearing exercises are encouraged in or endoscopic variceal ligation. patients with cirrhosis. e Precipitating causes of hepatic encephalopathy may Protein-calorie malnutrition is common in patients with include infection, sedating medications, volume deple- cirrhosis. Protein consumption is essential to prevent the cata- tion, or gastrointestinal bleeding; treatment involves bolic effects of chronic liver disease. Patients with cirrhosis addressing the precipitating cause and administering should consume 1.5 g of protein/d per kg of body weight. lactulose or rifaximin. Medications metabolized by the liver may require dosage HVC e Ultrasonography is the most effective means of identify- adjustments depending on cirrhosis severity. Patients with ing ascites; the serum -ascites albumin gradient and advanced cirrhosis (CTP class B or C) often require dosage

demonstrates right ventricular systolic pressures greater than benzodiazepines, should be avoided to prevent hepatic 50 mm Hg, which necessitates right-heart catheterization to encephalopathy. Patients should avoid consuming raw shell- confirm the diagnosis. Although portopulmonary hyperten- fish, which can transmit Vibrio vulnificus, an organism caus- sion was formerly a contraindication to liver transplantation, ing potentially fatal infection in patients with cirrhosis. patients with preserved right ventricular function who attain Metabolic bone disease is common in patients with cir- a mean pulmonary artery pressure less than 35 mm Hg with rhosis, and patients should be screened for osteoporosis. The vasodilator therapies can benefit from liver transplantation. development of osteoporosis in patients with cirrhosis is Prostacyclin analogues, phosphodiesterase inhibitors, and multifactorial and is associated with jaundice (negatively endothelin receptor antagonists have been used to treat por- affects osteoblast viability), hypogonadism, and decreased topulmonary hypertension. levels of insulin-like growth factor. Cholestasis also decreases absorption of vitamin D. Patients with osteoporosis are treated with calcium supplementation and antiresorptive e Upper endoscopy should be performed in patients with agents. Patients with esophageal varices should receive intra- cirrhosis to assess for esophageal varices; primary venous rather than oral bisphosphonates. Patients with prophylaxis to prevent bleeding includes nonselective osteopenia should be treated with supplemental calcium plus 6-blocker therapy (propranolol, nadolol, or carvedilol) vitamin D. Weight-bearing exercises are encouraged in or endoscopic variceal ligation. patients with cirrhosis. e Precipitating causes of hepatic encephalopathy may Protein-calorie malnutrition is common in patients with include infection, sedating medications, volume deple- cirrhosis. Protein consumption is essential to prevent the cata- tion, or gastrointestinal bleeding; treatment involves bolic effects of chronic liver disease. Patients with cirrhosis addressing the precipitating cause and administering should consume 1.5 g of protein/d per kg of body weight. lactulose or rifaximin. Medications metabolized by the liver may require dosage HVC e Ultrasonography is the most effective means of identify- adjustments depending on cirrhosis severity. Patients with ing ascites; the serum -ascites albumin gradient and advanced cirrhosis (CTP class B or C) often require dosage total protein levels in ascitic fluid help determine the adjustments, whereas patients with well-compensated cirrho-

HVC e Ultrasonography is the most effective means of identify- adjustments depending on cirrhosis severity. Patients with ing ascites; the serum -ascites albumin gradient and advanced cirrhosis (CTP class B or C) often require dosage total protein levels in ascitic fluid help determine the adjustments, whereas patients with well-compensated cirrho- cause of ascites. sis (CTP class A) may not. Patients with advanced cirrhosis have complex analgesic e Management of ascites involves a sodium-restricted diet prescribing needs. Narcotic analgesics can precipitate hepatic and diuretic therapy. encephalopathy. NSAIDs can impair renal perfusion, worsen e Anascitic-fluid neutrophil count of 250/uL (0.25 x 10°/L) kidney function, and exacerbate fluid retention. Acetaminophen or greater confirms the diagnosis of spontaneous bacterial up to 2000 mg daily is generally safe in patients with cirrhosis. peritonitis; initial treatment is with a third-generation Alternative approaches to pain control, including nonpharma- cephalosporin. cologic options (e.g., physical therapy, behavioral therapy, and e Hepatopulmonary syndrome should be suspected in local injection therapies) as indicated, should be considered. patients with portal hypertension who have dyspnea and hypoxemia; the diagnosis is confirmed by intrapul- monary shunting with agitated saline administration e Patients with chronic liver disease should be vaccinated

cause of ascites. sis (CTP class A) may not. Patients with advanced cirrhosis have complex analgesic e Management of ascites involves a sodium-restricted diet prescribing needs. Narcotic analgesics can precipitate hepatic and diuretic therapy. encephalopathy. NSAIDs can impair renal perfusion, worsen e Anascitic-fluid neutrophil count of 250/uL (0.25 x 10°/L) kidney function, and exacerbate fluid retention. Acetaminophen or greater confirms the diagnosis of spontaneous bacterial up to 2000 mg daily is generally safe in patients with cirrhosis. peritonitis; initial treatment is with a third-generation Alternative approaches to pain control, including nonpharma- cephalosporin. cologic options (e.g., physical therapy, behavioral therapy, and e Hepatopulmonary syndrome should be suspected in local injection therapies) as indicated, should be considered. patients with portal hypertension who have dyspnea and hypoxemia; the diagnosis is confirmed by intrapul- monary shunting with agitated saline administration e Patients with chronic liver disease should be vaccinated during echocardiography. against hepatitis A and B viruses and should receive pneumococcal vaccinations and annual influenza vaccination.

during echocardiography. against hepatitis A and B viruses and should receive pneumococcal vaccinations and annual influenza vaccination. Health Care Maintenance e Patients with cirrhosis should avoid alcohol, sedating drugs, opioids, and raw shellfish. in Patients With Chronic e Patients with cirrhosis should be screened for osteoporosis; Liver Disease confirmed osteoporosis should be treated with antire- Patients with chronic liver disease are at risk for severe com- sorptive agents. plications if they develop acute hepatitis. They should be vac- cinated against hepatitis A and B viruses if they are not immune. Nonresponse to vaccinations is more common in patients with cirrhosis, and postvaccination immunity should Solid and Cystic Liver Lesions be assessed. Patients with chronic liver disease should receive Benign liver lesions are typically discovered incidentally on annual influenza vaccination and pneumococcal vaccinations. abdominal imaging and are asymptomatic, with the excep- Other vaccinations should be given based on current recom- tions of liver abscesses or some lesions greater than 5 cm. Most mendations (see MKSAP 19 General Internal Medicine 2). liver lesions are diagnosed noninvasively with CT or MRI. Patients with cirrhosis should be counseled to strictly Percutaneous fine-needle aspiration of lesions is performed avoid alcohol. Sedating medications, such as opiates and when imaging is nondiagnostic and when the information 67

Disorders of the Liver obtained from aspiration will prompt a change in manage- Focal Nodular Hyperplasia ment. Risks of liver biopsy, including bleeding, perforation, Focal nodular hyperplasia (FNH) is the most common benign and death, are rare but must be considered. liver tumor and a frequent incidental finding. It is caused by a congenital arterial anomaly leading to a focal area of regenera- Hepatic Cysts tion that appears as a stellate scar on CT or MRI. CT or MRI Hepatic cysts are a common radiologic finding. Simple cysts with and without contrast can confirm the diagnosis. FNH are smooth with thin walls and anechoic features on ultra- does not have malignant potential or risk for bleeding and sonography. Patients with polycystic liver disease or autosomal does not require follow-up. In women with FNH who continue dominant polycystic kidney disease can present with numer- to use oral contraceptives, there is limited evidence to recom- ous liver cysts. Asymptomatic cysts are benign and require no mend liver ultrasonography every 2 to 3 years to assess for follow-up. Large cysts rarely present with abdominal pain and growth. can be treated with surgical defenestration or, if surgery is contraindicated, with cyst aspiration and sclerotherapy. Rarely, Hepatic Hemangiomas extensive polycystic liver disease may lead to portal hyperten- Hepatic hemangiomas are benign, common, and more fre- sion due to vascular obstruction or malnutrition due to gastric quent in women. Up to 20% of affected patients have multiple compression. Management options include surgical debulk- hemangiomas. Hepatic hemangiomas are rarely symptomatic, ing, but if this is not technically feasible, liver transplantation and, in most cases, symptoms that might be ascribed to a may be indicated. Cystadenomas are distinguished from sim- hemangioma are due to other causes. Hemangiomas do not ple cysts by the presence of thick, complex walls on ultra- have potential for malignancy, and spontaneous bleeding is sonography; they require surgical resection because of risk for rare. The diagnosis should be confirmed with MRI or CT with malignancy. contrast, which typically shows peripheral nodular enhance- ment and progressive centripetal contrast enhancement. Hepatic Adenomas Biopsies should be avoided because of bleeding risk. Hepatic Hepatic adenomas are rare liver neoplasms. They are associ- hemangiomas do not require intervention or follow-up except ated with oral contraceptives and are eight times more com- in the rare instance when they cause symptoms. mon in women than men. Other risk factors include androgen treatment, type 1 and 3 glycogen storage disease, and obesity. Hepatic Abscesses Although benign, hepatic adenomas, especially larger ones, may rupture, with resultant hemorrhage, or undergo malig- Pyogenic Liver Abscesses Pyogenic liver abscesses are complications of biliary tract nant transformation. Hepatic adenomas can be incidentally found on ultra- infections or portal venous spread of intra-abdominal infec-

obtained from aspiration will prompt a change in manage- Focal Nodular Hyperplasia ment. Risks of liver biopsy, including bleeding, perforation, Focal nodular hyperplasia (FNH) is the most common benign and death, are rare but must be considered. liver tumor and a frequent incidental finding. It is caused by a congenital arterial anomaly leading to a focal area of regenera- Hepatic Cysts tion that appears as a stellate scar on CT or MRI. CT or MRI Hepatic cysts are a common radiologic finding. Simple cysts with and without contrast can confirm the diagnosis. FNH are smooth with thin walls and anechoic features on ultra- does not have malignant potential or risk for bleeding and sonography. Patients with polycystic liver disease or autosomal does not require follow-up. In women with FNH who continue dominant polycystic kidney disease can present with numer- to use oral contraceptives, there is limited evidence to recom- ous liver cysts. Asymptomatic cysts are benign and require no mend liver ultrasonography every 2 to 3 years to assess for follow-up. Large cysts rarely present with abdominal pain and growth. can be treated with surgical defenestration or, if surgery is contraindicated, with cyst aspiration and sclerotherapy. Rarely, Hepatic Hemangiomas extensive polycystic liver disease may lead to portal hyperten- Hepatic hemangiomas are benign, common, and more fre- sion due to vascular obstruction or malnutrition due to gastric quent in women. Up to 20% of affected patients have multiple compression. Management options include surgical debulk- hemangiomas. Hepatic hemangiomas are rarely symptomatic, ing, but if this is not technically feasible, liver transplantation and, in most cases, symptoms that might be ascribed to a may be indicated. Cystadenomas are distinguished from sim- hemangioma are due to other causes. Hemangiomas do not ple cysts by the presence of thick, complex walls on ultra- have potential for malignancy, and spontaneous bleeding is sonography; they require surgical resection because of risk for rare. The diagnosis should be confirmed with MRI or CT with malignancy. contrast, which typically shows peripheral nodular enhance- ment and progressive centripetal contrast enhancement. Hepatic Adenomas Biopsies should be avoided because of bleeding risk. Hepatic Hepatic adenomas are rare liver neoplasms. They are associ- hemangiomas do not require intervention or follow-up except ated with oral contraceptives and are eight times more com- in the rare instance when they cause symptoms. mon in women than men. Other risk factors include androgen treatment, type 1 and 3 glycogen storage disease, and obesity. Hepatic Abscesses Although benign, hepatic adenomas, especially larger ones, may rupture, with resultant hemorrhage, or undergo malig- Pyogenic Liver Abscesses Pyogenic liver abscesses are complications of biliary tract nant transformation. Hepatic adenomas can be incidentally found on ultra- infections or portal venous spread of intra-abdominal infec- sonography, CT, or MRI. Hepatic adenomas can be differenti- tions, such as diverticulitis. Patients with pyogenic liver abscesses present with fever, right-upper-quadrant pain, and ated from focal nodular hyperplasia with MRI with bile-excreted contrast material, such as gadobenate dimeglu- malaise. Liver abscesses are typically polymicrobial, and the

sonography, CT, or MRI. Hepatic adenomas can be differenti- tions, such as diverticulitis. Patients with pyogenic liver abscesses present with fever, right-upper-quadrant pain, and ated from focal nodular hyperplasia with MRI with bile-excreted contrast material, such as gadobenate dimeglu- malaise. Liver abscesses are typically polymicrobial, and the mine or gadoxetate disodium, because they typically do not diagnosis is confirmed by radiologically guided aspiration. have normal biliary excretion. Biopsy is indicated only when Small abscesses (<3 cm) can be successfully treated by there is diagnostic uncertainty, but it may increase the risk for administration of broad-spectrum antibiotics. Larger abscesses are treated by aspiration or longer-term percutane- bleeding and should be performed only if the result will likely change management. ous catheter drainage in addition to broad-spectrum antibiot- Treatment depends on use of oral contraceptives and ics. Radiologically guided aspiration with catheter drainage is adenoma size. All patients taking oral contraceptives should usually successful; surgical excision of pyogenic hepatic discontinue those drugs and undergo follow-up CT or MRI abscesses is rarely needed.

Treatment depends on use of oral contraceptives and ics. Radiologically guided aspiration with catheter drainage is adenoma size. All patients taking oral contraceptives should usually successful; surgical excision of pyogenic hepatic discontinue those drugs and undergo follow-up CT or MRI abscesses is rarely needed. every 6 to 12 months to confirm stability or regression in lesion size. The duration of surveillance and treatment Amebic Liver Abscesses depends on subsequent imaging findings. In women not tak- Amebic abscesses of the liver are found in developing areas of ing oral contraceptives, hepatic adenomas 5 cm or smaller can the world or in persons who have emigrated from countries be managed with serial imaging every 6 months; however, where amebiasis is endemic. Intestinal infection with amoe- with larger adenomas, the risk for hemorrhage or malignant bae can result in invasion of the portal vein and migration to transformation is elevated and surgical resection should be the liver. Symptoms of amebic liver abscesses include right- considered. Men with hepatic adenomas of any size are at upper-quadrant abdominal pain and fever. Amebic liver increased risk for malignant transformation, and resection is abscess is diagnosed by hepatic imaging and serologic testing; recommended. aspiration is usually not required. Treatment of the hepatic Pregnancy can result in adenoma growth, and resection infection with metronidazole or tinidazole should be accom- or ablation of adenomas can be considered if pregnancy is panied by eradication of the always-coexistent intestinal infec- contemplated. tion with paromomycin. 68

Disorders of the Liver Hepatic Granulomas TABLE 40. Populations Recommended for Hepatocellular Granulomas are focal inflammatory lesions that consist of Carcinoma Screening and Surveillance? mononuclear cells, lymphocytes, and fibroblasts. Hepatic Cirrhosis granulomatous disease can be seen with infections, such as Asian descent + male sex + age >40 years in HBV-infected tuberculosis, fungal infection (e.g., coccidioidomycosis, histo- patients plasmosis), Q fever, cytomegalovirus infection, Epstein-Barr Asian descent + female sex + age >50 years in HBV-infected virus infection, and viral hepatitis. Granulomas also occur | patients with inflammatory disorders (e.g., sarcoidosis), medications Sub-Saharan African descent + age >20 years in HBV-infected (e.g., allopurinol), and malignancies (e.g., lymphoma). patients

plasmosis), Q fever, cytomegalovirus infection, Epstein-Barr Asian descent + female sex + age >50 years in HBV-infected virus infection, and viral hepatitis. Granulomas also occur | patients with inflammatory disorders (e.g., sarcoidosis), medications Sub-Saharan African descent + age >20 years in HBV-infected (e.g., allopurinol), and malignancies (e.g., lymphoma). patients Symptoms of hepatic granulomas are nonspecific and Persistent inflammatory activity (defined as elevated ALT level | and HBV DNA level >10,000 IU/mL for at least a few years) in include fever, malaise, and night sweats in addition to symptoms HBV-infected patients seen with the underlying disorder. Hepatic sarcoidosis may Family history of hepatocellular carcinoma in HBV-infected occur in patients with other systemic manifestations of sarcoido- | patients sis but can be the only manifestation of sarcoidosis (for further | Males with primary biliary cholangitis discussion of sarcoidosis, see MKSAP 19 Rheumatology). Portal hypertension can result from obliteration of small portal veins. ALT = alanine aminotransferase; HBV = hepatitis B virus.

Symptoms of hepatic granulomas are nonspecific and Persistent inflammatory activity (defined as elevated ALT level | and HBV DNA level >10,000 IU/mL for at least a few years) in include fever, malaise, and night sweats in addition to symptoms HBV-infected patients seen with the underlying disorder. Hepatic sarcoidosis may Family history of hepatocellular carcinoma in HBV-infected occur in patients with other systemic manifestations of sarcoido- | patients sis but can be the only manifestation of sarcoidosis (for further | Males with primary biliary cholangitis discussion of sarcoidosis, see MKSAP 19 Rheumatology). Portal hypertension can result from obliteration of small portal veins. ALT = alanine aminotransferase; HBV = hepatitis B virus. In patients with hepatic sarcoidosis, 6% to 8% progress to cir- *Hepatocellular carcinoma screening should be performed with ultrasonography with or without a-fetoprotein every 6 months. Cross-sectional imaging can be thosis, although liver failure and the need for liver transplan- used in cases in which ultrasonography is unreliable or is expected to be unreliable. tation are rare.

In patients with hepatic sarcoidosis, 6% to 8% progress to cir- *Hepatocellular carcinoma screening should be performed with ultrasonography with or without a-fetoprotein every 6 months. Cross-sectional imaging can be thosis, although liver failure and the need for liver transplan- used in cases in which ultrasonography is unreliable or is expected to be unreliable. tation are rare. Alkaline phosphatase and aminotransferase levels can be elevated regardless of cause. No single test can diagnose hepatic meeting the Milan criteria and with portal hypertension or sarcoidosis. Biopsy may be necessary in specific instances. jaundice. The Milan criteria are as follows: up to three liver Treatment of hepatic granulomas depends on the cause. lesions 3 cm or smaller or one lesion 5 cm or smaller, without Infectious causes should be treated if identified. Potential apparent vascular invasion and without extrahepatic spread. offending medications should be discontinued. Patients with a tumor burden that exceeds the Milan criteria Treatment of hepatic sarcoidosis is not necessary if there can potentially undergo locoregional therapy to “downsize” are no symptoms and liver chemistries are only mildly elevated. tumor burden to within Milan criteria, permitting considera- Ursodeoxycholic acid or glucocorticoids may be considered if tion of liver transplantation. Locoregional therapies include symptomis exist or liver chemistries are substantially elevated. radiofrequency or microwave ablation, transarterial chem- oembolization, and transarterial radioembolization. Patients Hepatocellular Carcinoma who are not surgical or liver transplant candidates should be Hepatocellular carcinoma (HCC) is the most common liver considered for locoregional therapy if they lack macrovascular tumor in patients with cirrhosis, the fifth most common cause invasion (tumor thrombus) or extrahepatic spread. Decisions of cancer worldwide, and the second most common cause of about locoregional therapy are increasingly made through cancer-related death worldwide. More than 80% of patients multidisciplinary tumor boards. with HCC have cirrhosis. Systemic therapy options for patients with macrovascu- Patients with cirrhosis, regardless of cause, require sur- lar invasion or evidence of extrahepatic disease have been veillance liver ultrasonography with or without o-fetoprotein developed. Sorafenib, an oral multikinase inhibitor, provides measurement every 6 months. This approach leads to early a modest survival benefit in patients who have HCC with diagnosis, increased rate of curative treatment, and improved macrovascular invasion or metastatic disease. Other FDA- 3-year survival rates. Patients with HBV infection can develop approved drugs for advanced HCC include lenvatinib, HCC even without cirrhosis. Surveillance for HCC is recom- regorafenib, and nivolumab; the latter is an intravenous mended even in the absence of cirrhosis in individuals with humanized monoclonal antibody against the programmed HBV who are at high risk (patients with a family history of cell death receptor. The FDA has approved the combination HCC, patients from sub-Saharan Africa and age >20 years, of atezolizumab and bevacizumab as therapy for hepatocel- Asian men >40 years, and Asian women >50 years) (Table 40). lular carcinoma. HCC is typically diagnosed without biopsy with the use of multiphase contrast-enhanced CT or MRI in patients with cir- rhosis and a lesion measuring at least 1 cm. Biopsy may be e Asymptomatic hepatic cysts are benign and require no needed for lesions that are indeterminant on imaging. follow-up. Many societies have issued guidelines for managing HCC. e Patients with hepatic adenomas taking oral contraceptives Patients with CTP class A cirrhosis, without significant portal should discontinue those drugs and undergo follow-up hypertension or jaundice, and with a singular lesion 5 cm or imaging to confirm stability or regression in lesion size. smaller should be considered for curative resection. Liver (Continued) transplantation should be considered in patients with HCC

Alkaline phosphatase and aminotransferase levels can be elevated regardless of cause. No single test can diagnose hepatic meeting the Milan criteria and with portal hypertension or sarcoidosis. Biopsy may be necessary in specific instances. jaundice. The Milan criteria are as follows: up to three liver Treatment of hepatic granulomas depends on the cause. lesions 3 cm or smaller or one lesion 5 cm or smaller, without Infectious causes should be treated if identified. Potential apparent vascular invasion and without extrahepatic spread. offending medications should be discontinued. Patients with a tumor burden that exceeds the Milan criteria Treatment of hepatic sarcoidosis is not necessary if there can potentially undergo locoregional therapy to “downsize” are no symptoms and liver chemistries are only mildly elevated. tumor burden to within Milan criteria, permitting considera- Ursodeoxycholic acid or glucocorticoids may be considered if tion of liver transplantation. Locoregional therapies include symptomis exist or liver chemistries are substantially elevated. radiofrequency or microwave ablation, transarterial chem- oembolization, and transarterial radioembolization. Patients Hepatocellular Carcinoma who are not surgical or liver transplant candidates should be Hepatocellular carcinoma (HCC) is the most common liver considered for locoregional therapy if they lack macrovascular tumor in patients with cirrhosis, the fifth most common cause invasion (tumor thrombus) or extrahepatic spread. Decisions of cancer worldwide, and the second most common cause of about locoregional therapy are increasingly made through cancer-related death worldwide. More than 80% of patients multidisciplinary tumor boards. with HCC have cirrhosis. Systemic therapy options for patients with macrovascu- Patients with cirrhosis, regardless of cause, require sur- lar invasion or evidence of extrahepatic disease have been veillance liver ultrasonography with or without o-fetoprotein developed. Sorafenib, an oral multikinase inhibitor, provides measurement every 6 months. This approach leads to early a modest survival benefit in patients who have HCC with diagnosis, increased rate of curative treatment, and improved macrovascular invasion or metastatic disease. Other FDA- 3-year survival rates. Patients with HBV infection can develop approved drugs for advanced HCC include lenvatinib, HCC even without cirrhosis. Surveillance for HCC is recom- regorafenib, and nivolumab; the latter is an intravenous mended even in the absence of cirrhosis in individuals with humanized monoclonal antibody against the programmed HBV who are at high risk (patients with a family history of cell death receptor. The FDA has approved the combination HCC, patients from sub-Saharan Africa and age >20 years, of atezolizumab and bevacizumab as therapy for hepatocel- Asian men >40 years, and Asian women >50 years) (Table 40). lular carcinoma. HCC is typically diagnosed without biopsy with the use of multiphase contrast-enhanced CT or MRI in patients with cir- rhosis and a lesion measuring at least 1 cm. Biopsy may be e Asymptomatic hepatic cysts are benign and require no needed for lesions that are indeterminant on imaging. follow-up. Many societies have issued guidelines for managing HCC. e Patients with hepatic adenomas taking oral contraceptives Patients with CTP class A cirrhosis, without significant portal should discontinue those drugs and undergo follow-up hypertension or jaundice, and with a singular lesion 5 cm or imaging to confirm stability or regression in lesion size. smaller should be considered for curative resection. Liver (Continued) transplantation should be considered in patients with HCC 69

Disorders of the Liver HCV, however, is relatively rare; less than 5% of women with HCV viremia transmit HCV to their children. No specific steps ¢ Focal nodular hyperplasia does not have malignant can be taken to eliminate the risk for vertical transmission of potential or a risk for bleeding and does not require HCV. Antiviral therapy for HCV should not be undertaken dur- follow-up. ing pregnancy. e Patients with cirrhosis and high-risk patients with hep- HBV carries a higher risk for vertical transmission, which atitis B virus infection require hepatocellular carcinoma can be as high as 90% among women with HBe antigen- surveillance using liver ultrasonography with or without positive infection; high HBV DNA levels also increase the risk o-fetoprotein measurement every 6 months. for transmission. Pregnant women with an HBV DNA level exceeding 200,000 IU/mL between gestational weeks 24 and 28 should start oral antiviral treatment to prevent vertical Liver Transplantation transmission. Oral antiviral agents approved in pregnancy Referral for liver transplantation is indicated in patients whose include lamivudine, telbivudine, and tenofovir. Breastfeeding MELD score is 15 or greater because transplantation provides a is not contraindicated during antiviral treatment. Passive survival advantage in these patients. Patients with decompen- immunization with HBV immune globulin and active HBV sated cirrhosis, including ascites, spontaneous bacterial peri- vaccination should be administered to newborns within tonitis, esophageal variceal bleeding, hepatic encephalopathy, 12 hours of delivery. These measures reduce vertical transmis- jaundice, or hepatocellular carcinoma, should also be consid- sion rates by 95%. ered for referral. Patients should generally be abstinent from Women with autoimmune hepatitis who become preg- alcohol, although transplant centers may differ in their nant typically continue using prednisone and/or azathioprine, requirements for sobriety duration and chemical-dependency which are considered safe during pregnancy. The risk for a treatment. Other factors important in candidate selection flare of autoimmune hepatitis due to stopping these medica- include adequate social support, ability to adhere to medical tions is considered a greater risk. treatment, and absence of significant cardiopulmonary and Several liver diseases are unique to pregnancy and can psychiatric comorbidities and active infectious diseases. affect the health of mother and fetus. During the first trimes- Appropriate candidates are placed on the national waiting ter, hyperemesis gravidarum occurs when prolonged, intrac- list, with the highest priority given to patients with acute liver table vomiting results in fluid and electrolyte abnormalities. failure and high MELD-Na scores. MELD exception points Hepatic aminotransferase levels are elevated in up to 50% of may also be added in the presence of specific disorders, cases of hyperemesis gravidarum, but jaundice is rare. including hepatocellular carcinoma, portopulmonary hyper- Laboratory abnormalities typically resolve when vomiting tension, hepatopulmonary syndrome, familial amyloidotic abates. Pyridoxine and antiemetic medications can alleviate polyneuropathy, primary hyperoxaluria, cystic fibrosis, and symptoms of hyperemesis gravidarum. cholangiocarcinoma. Intrahepatic cholestasis of pregnancy is presumed to result The average 1- and 5-year survival rates after liver trans- from cholestatic effects of increased levels of pregnancy-related plantation are 92% and 75% to 85%, respectively. Recipients hormones. Risk for this condition can be elevated in women of require lifelong immunosuppression, most commonly with South American descent, women pregnant with twins, and tacrolimus or cyclosporine. Recipients have increased risk women with a history of liver disease. Intrahepatic cholestasis of for diabetes, hypertension, hyperlipidemia, chronic kidney pregnancy typically presents in the second to third trimesters. disease, and malignancy secondary to immunosuppressive Symptoms include pruritus in most patients and jaundice in 10% medications. to 25%. Serum bile acid levels are elevated and help establish the diagnosis. Fetal complications, including placental insufficiency, e Referral to a transplant center is indicated for patients premature labor, and sudden fetal death, are more common in with acute liver failure or patients with cirrhosis with a intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid Model for End-Stage Liver Disease score of 15 or greater relieves pruritus and improves fetal outcomes. Fetal mortality is or evidence of decompensated cirrhosis. increased late in gestation. Delivery is typically induced at 36 to 38 weeks’ gestation in women with proven disease. The most serious pregnancy-related liver diseases are Pregnancy-Related Liver Diseases HELLP (hemolysis, elevated liver enzymes, and low platelets) Pregnancy results in physiologic changes that mimic chronic syndrome and acute fatty liver of pregnancy. They occur in the liver disease. Altered hormonal states and increasing circula- third trimester of pregnancy and are associated with high rates tory volume can lead to lower-extremity edema, palmar ery- of maternal and fetal mortality. Definitive therapy for these thema, and spider angiomata. conditions is delivery of the fetus. Pregnant women with preexisting HCV and HBV infection HELLP syndrome is a severe complication of preeclamp- can transmit the virus to the newborn. Vertical transmission of sia. It typically presents with abdominal pain, nausea with

HCV, however, is relatively rare; less than 5% of women with HCV viremia transmit HCV to their children. No specific steps ¢ Focal nodular hyperplasia does not have malignant can be taken to eliminate the risk for vertical transmission of potential or a risk for bleeding and does not require HCV. Antiviral therapy for HCV should not be undertaken dur- follow-up. ing pregnancy. e Patients with cirrhosis and high-risk patients with hep- HBV carries a higher risk for vertical transmission, which atitis B virus infection require hepatocellular carcinoma can be as high as 90% among women with HBe antigen- surveillance using liver ultrasonography with or without positive infection; high HBV DNA levels also increase the risk o-fetoprotein measurement every 6 months. for transmission. Pregnant women with an HBV DNA level exceeding 200,000 IU/mL between gestational weeks 24 and 28 should start oral antiviral treatment to prevent vertical Liver Transplantation transmission. Oral antiviral agents approved in pregnancy Referral for liver transplantation is indicated in patients whose include lamivudine, telbivudine, and tenofovir. Breastfeeding MELD score is 15 or greater because transplantation provides a is not contraindicated during antiviral treatment. Passive survival advantage in these patients. Patients with decompen- immunization with HBV immune globulin and active HBV sated cirrhosis, including ascites, spontaneous bacterial peri- vaccination should be administered to newborns within tonitis, esophageal variceal bleeding, hepatic encephalopathy, 12 hours of delivery. These measures reduce vertical transmis- jaundice, or hepatocellular carcinoma, should also be consid- sion rates by 95%. ered for referral. Patients should generally be abstinent from Women with autoimmune hepatitis who become preg- alcohol, although transplant centers may differ in their nant typically continue using prednisone and/or azathioprine, requirements for sobriety duration and chemical-dependency which are considered safe during pregnancy. The risk for a treatment. Other factors important in candidate selection flare of autoimmune hepatitis due to stopping these medica- include adequate social support, ability to adhere to medical tions is considered a greater risk. treatment, and absence of significant cardiopulmonary and Several liver diseases are unique to pregnancy and can psychiatric comorbidities and active infectious diseases. affect the health of mother and fetus. During the first trimes- Appropriate candidates are placed on the national waiting ter, hyperemesis gravidarum occurs when prolonged, intrac- list, with the highest priority given to patients with acute liver table vomiting results in fluid and electrolyte abnormalities. failure and high MELD-Na scores. MELD exception points Hepatic aminotransferase levels are elevated in up to 50% of may also be added in the presence of specific disorders, cases of hyperemesis gravidarum, but jaundice is rare. including hepatocellular carcinoma, portopulmonary hyper- Laboratory abnormalities typically resolve when vomiting tension, hepatopulmonary syndrome, familial amyloidotic abates. Pyridoxine and antiemetic medications can alleviate polyneuropathy, primary hyperoxaluria, cystic fibrosis, and symptoms of hyperemesis gravidarum. cholangiocarcinoma. Intrahepatic cholestasis of pregnancy is presumed to result The average 1- and 5-year survival rates after liver trans- from cholestatic effects of increased levels of pregnancy-related plantation are 92% and 75% to 85%, respectively. Recipients hormones. Risk for this condition can be elevated in women of require lifelong immunosuppression, most commonly with South American descent, women pregnant with twins, and tacrolimus or cyclosporine. Recipients have increased risk women with a history of liver disease. Intrahepatic cholestasis of for diabetes, hypertension, hyperlipidemia, chronic kidney pregnancy typically presents in the second to third trimesters. disease, and malignancy secondary to immunosuppressive Symptoms include pruritus in most patients and jaundice in 10% medications. to 25%. Serum bile acid levels are elevated and help establish the diagnosis. Fetal complications, including placental insufficiency, e Referral to a transplant center is indicated for patients premature labor, and sudden fetal death, are more common in with acute liver failure or patients with cirrhosis with a intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid Model for End-Stage Liver Disease score of 15 or greater relieves pruritus and improves fetal outcomes. Fetal mortality is or evidence of decompensated cirrhosis. increased late in gestation. Delivery is typically induced at 36 to 38 weeks’ gestation in women with proven disease. The most serious pregnancy-related liver diseases are Pregnancy-Related Liver Diseases HELLP (hemolysis, elevated liver enzymes, and low platelets) Pregnancy results in physiologic changes that mimic chronic syndrome and acute fatty liver of pregnancy. They occur in the liver disease. Altered hormonal states and increasing circula- third trimester of pregnancy and are associated with high rates tory volume can lead to lower-extremity edema, palmar ery- of maternal and fetal mortality. Definitive therapy for these thema, and spider angiomata. conditions is delivery of the fetus. Pregnant women with preexisting HCV and HBV infection HELLP syndrome is a severe complication of preeclamp- can transmit the virus to the newborn. Vertical transmission of sia. It typically presents with abdominal pain, nausea with 70

Disorders of the Gallbladder and Bile Ducts vomiting, pruritus, and jaundice. Blood pressure, fluids and as thrombosis of the hepatic veins. The syndrome may be asso- electrolytes, kidney function, and coagulopathy may require ciated with myeloproliferative neoplasms, pregnancy, oral careful management in the perinatal state; patients should contraceptive use, inflammatory bowel disease, or inherited be managed in high-risk obstetric units. Although delivery is thrombophilias. Underlying malignancy, especially hepatocel- the definitive therapy, the maternal condition may continue to lular carcinoma, may also be causative. Characteristic symp- worsen in the immediate postpartum period. Resolution typi- toms include hepatomegaly, ascites, and right-upper-quadrant cally occurs within days after delivery. Rarely, liver transplan- abdominal pain. Budd-Chiari syndrome is typically diagnosed tation may be required if liver recovery is not seen. HELLP can by Doppler ultrasonography in the appropriate clinical set- recur in up to 25% of subsequent pregnancies. ting. The caudate lobe of the liver is hypertrophied because Acute fatty liver of pregnancy presents with symptoms caudate venous outflow is directly into the inferior vena cava similar to those of HELLP syndrome. Indicators of liver failure, rather than through the hepatic veins. Long-term anticoagu- including hypoglycemia and coagulopathy, can be seen. lation is required in patients with Budd-Chiari syndrome, Affected patients may require transfer to a liver transplant although bleeding risks are significant in patients with acute center. Prompt delivery of the fetus once the diagnosis is rec- or chronic liver disease, portal hypertension, and esophageal ognized typically results in improvement of the mother’s med- varices. Angioplasty of the hepatic veins and/or TIPS place- ical condition in 48 to 72 hours. Acute fatty liver of pregnancy ment can be used to reestablish adequate hepatic venous can recur in subsequent pregnancies. It is associated with drainage. If liver failure develops, liver transplantation may long-chain 3-hydroxyacyl coenzyme A dehydrogenase defi- be considered. ciency, and affected women and their offspring should be screened for this deficiency. e Portal vein thrombosis is common in patients with decompensated cirrhosis and is a consequence of poor e Measures to reduce vertical transmission of hepatitis B flow through the portal veins. virus include administering hepatitis B virus immune e Characteristic symptoms of Budd-Chiari syndrome include globulin and immediate vaccination of newborns. hepatomegaly, ascites, and right-upper-quadrant abdom- e The most serious liver complications of pregnancy occur inal pain. in the third trimester and include HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and acute fatty liver of pregnancy; both are managed in high-risk obstetric units and with early delivery. Disorders of the Gallbladder and Bile Ducts Vascular Diseases of the Liver Asymptomatic Gallstones Portal Vein Thrombosis Gallstones can be characterized as cholesterol stones or pig- Portal vein thrombosis is common in patients with decom- ment stones. Cholesterol stones result from supersaturation of pensated cirrhosis and is due to slow flow through the portal bile with cholesterol; they account for approximately 75% of veins rather than hypercoagulability; it may occasionally gallstones in the United States. Risk factors for cholesterol occur in patients without cirrhosis. It is typically diagnosed stones include older age, female sex (twice as likely in women by abdominal Doppler ultrasonography; contrast-enhanced as in men), American Indian ethnicity, Western diet, preg- CT or MRI should be completed to delineate extent of throm- nancy, rapid weight loss, obesity, total parenteral nutrition, bosis and to assess for tumor thrombosis. Chronic portal and estrogen supplementation. Predisposing factors for pig- vein thrombosis is typically asymptomatic and does not usu- ment stones include chronic hemolysis, ineffective erythro- ally require anticoagulant therapy unless thrombophilia, poiesis, Crohn disease, cirrhosis, biliary stasis, and bacterial bowel ischemia, or progression of thrombus is present. biliary infections. Patients with acute portal vein thrombosis should receive Gallstones are commonly discovered at abdominal ultra- anticoagulation unless risk of bleeding is very prohibitive. sonography (Figure 35) and CT performed for unrelated Direct oral anticoagulants or low-molecular-weight heparin reasons. are the anticoagulants of choice. Systemic thrombolytic Incidental gallstones are typically asymptomatic, and pro- therapy and catheter-directed thrombolysis are rarely phylactic cholecystectomy is generally not recommended. indicated. Cholecystectomy is indicated in asymptomatic patients with characteristics posing a high risk for gallbladder cancer: gall- Budd-Chiari Syndrome stones larger than 3 cm, porcelain gallbladder (intramural Budd-Chiari syndrome describes any disease process that calcification of gallbladder wall), or gallbladder polyps larger obstructs the normal outflow of blood from the liver, usually than 1 cm.

vomiting, pruritus, and jaundice. Blood pressure, fluids and as thrombosis of the hepatic veins. The syndrome may be asso- electrolytes, kidney function, and coagulopathy may require ciated with myeloproliferative neoplasms, pregnancy, oral careful management in the perinatal state; patients should contraceptive use, inflammatory bowel disease, or inherited be managed in high-risk obstetric units. Although delivery is thrombophilias. Underlying malignancy, especially hepatocel- the definitive therapy, the maternal condition may continue to lular carcinoma, may also be causative. Characteristic symp- worsen in the immediate postpartum period. Resolution typi- toms include hepatomegaly, ascites, and right-upper-quadrant cally occurs within days after delivery. Rarely, liver transplan- abdominal pain. Budd-Chiari syndrome is typically diagnosed tation may be required if liver recovery is not seen. HELLP can by Doppler ultrasonography in the appropriate clinical set- recur in up to 25% of subsequent pregnancies. ting. The caudate lobe of the liver is hypertrophied because Acute fatty liver of pregnancy presents with symptoms caudate venous outflow is directly into the inferior vena cava similar to those of HELLP syndrome. Indicators of liver failure, rather than through the hepatic veins. Long-term anticoagu- including hypoglycemia and coagulopathy, can be seen. lation is required in patients with Budd-Chiari syndrome, Affected patients may require transfer to a liver transplant although bleeding risks are significant in patients with acute center. Prompt delivery of the fetus once the diagnosis is rec- or chronic liver disease, portal hypertension, and esophageal ognized typically results in improvement of the mother’s med- varices. Angioplasty of the hepatic veins and/or TIPS place- ical condition in 48 to 72 hours. Acute fatty liver of pregnancy ment can be used to reestablish adequate hepatic venous can recur in subsequent pregnancies. It is associated with drainage. If liver failure develops, liver transplantation may long-chain 3-hydroxyacyl coenzyme A dehydrogenase defi- be considered. ciency, and affected women and their offspring should be screened for this deficiency. e Portal vein thrombosis is common in patients with decompensated cirrhosis and is a consequence of poor e Measures to reduce vertical transmission of hepatitis B flow through the portal veins. virus include administering hepatitis B virus immune e Characteristic symptoms of Budd-Chiari syndrome include globulin and immediate vaccination of newborns. hepatomegaly, ascites, and right-upper-quadrant abdom- e The most serious liver complications of pregnancy occur inal pain. in the third trimester and include HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome and acute fatty liver of pregnancy; both are managed in high-risk obstetric units and with early delivery. Disorders of the Gallbladder and Bile Ducts Vascular Diseases of the Liver Asymptomatic Gallstones Portal Vein Thrombosis Gallstones can be characterized as cholesterol stones or pig- Portal vein thrombosis is common in patients with decom- ment stones. Cholesterol stones result from supersaturation of pensated cirrhosis and is due to slow flow through the portal bile with cholesterol; they account for approximately 75% of veins rather than hypercoagulability; it may occasionally gallstones in the United States. Risk factors for cholesterol occur in patients without cirrhosis. It is typically diagnosed stones include older age, female sex (twice as likely in women by abdominal Doppler ultrasonography; contrast-enhanced as in men), American Indian ethnicity, Western diet, preg- CT or MRI should be completed to delineate extent of throm- nancy, rapid weight loss, obesity, total parenteral nutrition, bosis and to assess for tumor thrombosis. Chronic portal and estrogen supplementation. Predisposing factors for pig- vein thrombosis is typically asymptomatic and does not usu- ment stones include chronic hemolysis, ineffective erythro- ally require anticoagulant therapy unless thrombophilia, poiesis, Crohn disease, cirrhosis, biliary stasis, and bacterial bowel ischemia, or progression of thrombus is present. biliary infections. Patients with acute portal vein thrombosis should receive Gallstones are commonly discovered at abdominal ultra- anticoagulation unless risk of bleeding is very prohibitive. sonography (Figure 35) and CT performed for unrelated Direct oral anticoagulants or low-molecular-weight heparin reasons. are the anticoagulants of choice. Systemic thrombolytic Incidental gallstones are typically asymptomatic, and pro- therapy and catheter-directed thrombolysis are rarely phylactic cholecystectomy is generally not recommended. indicated. Cholecystectomy is indicated in asymptomatic patients with characteristics posing a high risk for gallbladder cancer: gall- Budd-Chiari Syndrome stones larger than 3 cm, porcelain gallbladder (intramural Budd-Chiari syndrome describes any disease process that calcification of gallbladder wall), or gallbladder polyps larger obstructs the normal outflow of blood from the liver, usually than 1 cm. 71

Disorders of the Gallbladder and Bile Ducts tenderness in the right upper quadrant. A positive Murphy sign may be present. Laboratory studies may show leukocyto- sis; liver chemistries are often normal or minimally elevated unless complications such as common bile duct obstruction or cholangitis are present. Acute cholecystitis is suggested by ultrasound showing gallbladder wall thickening and/or edema and a sonographic Murphy sign (arrest of respiration with compression by the ultrasound probe). Lack of gallbladder filling on hepatobiliary iminodiacetic acid scanning supports this diagnosis. This test is appropriate in the setting of a high clinical likelihood of acute cholecystitis but a negative or inde- terminate ultrasound finding. Treatment includes analgesia, intravenous antibiotics with gram-negative and anaerobic coverage, and cholecystec- tomy. Emergency surgery is necessary for suspected gallblad- FIGURE 35. Ultrasound shows the liver (/eft) and the gallbladder in long axis der perforation or emphysematous cholecystitis (infection of with multiple stones present. The stones appear hyperechoic (white) with shadowing artifact posteriorly, consistent with cholelithiasis. The lumen of a normal the gallbladder wall with gas-forming organisms, such as gallbladder should appear anechoic (black). It is important to scan through the Clostridium perfringens). Most patients should undergo chol- gallbladder to ensure that the entire lumen is visualized before determining ecystectomy during initial hospitalization. Patients with high whether stones are absent. An indeterminate study would occur if the gallbladder surgical risk who respond to antibiotics can be reassessed later cannot be completely visualized, usually because of underdistention secondary to to determine whether their surgical risk has decreased. In lack of fasting. patients who are not good surgical candidates and do not respond to antibiotics, percutaneous cholecystostomy tube or endoscopic drainage can be pursued. HVC e Asymptomatic gallstones discovered incidentally do not require cholecystectomy except in the setting of a high risk for gallbladder cancer (gallstones >3 cm, porcelain e Cholecystitis can be diagnosed by suggestive clinical gallbladder, or gallbladder polyps >1 cm). findings and ultrasound showing gallbladder-wall thickening or edema and sonographic Murphy sign.

tenderness in the right upper quadrant. A positive Murphy sign may be present. Laboratory studies may show leukocyto- sis; liver chemistries are often normal or minimally elevated unless complications such as common bile duct obstruction or cholangitis are present. Acute cholecystitis is suggested by ultrasound showing gallbladder wall thickening and/or edema and a sonographic Murphy sign (arrest of respiration with compression by the ultrasound probe). Lack of gallbladder filling on hepatobiliary iminodiacetic acid scanning supports this diagnosis. This test is appropriate in the setting of a high clinical likelihood of acute cholecystitis but a negative or inde- terminate ultrasound finding. Treatment includes analgesia, intravenous antibiotics with gram-negative and anaerobic coverage, and cholecystec- tomy. Emergency surgery is necessary for suspected gallblad- FIGURE 35. Ultrasound shows the liver (/eft) and the gallbladder in long axis der perforation or emphysematous cholecystitis (infection of with multiple stones present. The stones appear hyperechoic (white) with shadowing artifact posteriorly, consistent with cholelithiasis. The lumen of a normal the gallbladder wall with gas-forming organisms, such as gallbladder should appear anechoic (black). It is important to scan through the Clostridium perfringens). Most patients should undergo chol- gallbladder to ensure that the entire lumen is visualized before determining ecystectomy during initial hospitalization. Patients with high whether stones are absent. An indeterminate study would occur if the gallbladder surgical risk who respond to antibiotics can be reassessed later cannot be completely visualized, usually because of underdistention secondary to to determine whether their surgical risk has decreased. In lack of fasting. patients who are not good surgical candidates and do not respond to antibiotics, percutaneous cholecystostomy tube or endoscopic drainage can be pursued. HVC e Asymptomatic gallstones discovered incidentally do not require cholecystectomy except in the setting of a high risk for gallbladder cancer (gallstones >3 cm, porcelain e Cholecystitis can be diagnosed by suggestive clinical gallbladder, or gallbladder polyps >1 cm). findings and ultrasound showing gallbladder-wall thickening or edema and sonographic Murphy sign. e Treatment of acute cholecystitis includes analgesia, intra- Biliary Colic venous antibiotics with gram-negative and anaerobic Biliary colic results from contraction of the gallbladder in the coverage, and cholecystectomy during initial hospitaliza- presence of an obstructed cystic duct, usually by a gallstone. tion; percutaneous cholecystostomy tube or endoscopic Pain is typically of acute onset, lasts 30 minutes to 6 hours, is drainage can be pursued in patients with high surgical severe and steady, and is located in the right upper quadrant or risk. epigastrium. Pain may radiate to the right shoulder and is

e Treatment of acute cholecystitis includes analgesia, intra- Biliary Colic venous antibiotics with gram-negative and anaerobic Biliary colic results from contraction of the gallbladder in the coverage, and cholecystectomy during initial hospitaliza- presence of an obstructed cystic duct, usually by a gallstone. tion; percutaneous cholecystostomy tube or endoscopic Pain is typically of acute onset, lasts 30 minutes to 6 hours, is drainage can be pursued in patients with high surgical severe and steady, and is located in the right upper quadrant or risk. epigastrium. Pain may radiate to the right shoulder and is associated with nausea, vomiting, and diaphoresis. Symptoms may be precipitated by meals, which cause gallbladder con- Acalculous Cholecystitis traction. Constant, unremitting abdominal pain is not usually Acalculous cholecystitis typically occurs in critically ill associated with biliary colic. patients and results from gallbladder ischemia, which can be Patients with typical biliary colic symptoms and gall- complicated by enteric bacterial infection. Risk factors stones on imaging should undergo cholecystectomy because of include cardiac surgery, sepsis, burns, and vasculitis. In alert

associated with biliary colic. patients and results from gallbladder ischemia, which can be Patients with typical biliary colic symptoms and gall- complicated by enteric bacterial infection. Risk factors stones on imaging should undergo cholecystectomy because of include cardiac surgery, sepsis, burns, and vasculitis. In alert an increased risk for future complications, including choledo- patients, the presentation is pain, similar to that seen in chol- cholithiasis, cholangitis, and pancreatitis. ecystitis related to gallstones. In sedated or mechanically ventilated patients, it may present with leukocytosis, jaun- dice, and sepsis. Diagnosis is made with ultrasound showing e Patients with typical biliary colic symptoms and gall- gallbladder-wall thickening, pericholecystic fluid, gallblad- stones on imaging should undergo cholecystectomy. der distention, or gallbladder-wall pneumatosis without stones (Figure 36). Treatment entails intravenous antibiotics to cover enteric Acute Cholecystitis bacteria and cholecystectomy. A percutaneous cholecystos- Acute cholecystitis is due to cystic duct obstruction and gall- tomy tube may be needed for unstable patients or poor bladder inflammation, often accompanied by gallbladder surgical candidates. Endoscopic gallbladder drainage can be infection. Patients present with severe right-upper-quadrant considered. The mortality rate for untreated acalculous chol- or epigastric pain lasting longer than 6 hours, with fever and ecystitis is as high as 75%. 72

Disorders of the Gallbladder and Bile Ducts LONG LiveRRT & Pm a O-Fra 4.0 mH Common Bile Duct Stones — and Cholangitis Common bile duct stones are a leading cause of obstructive jaundice and pancreatitis. Although 20% of common duct stones pass spontaneously and less than 50% of patients develop symptoms, stone extraction should be offered to most patients. Symptoms of common bile duct stones include jaundice and abdominal pain due to obstruction of bile flow. Common duct stones may be visualized by transabdominal ultrasonography. In the absence of visualization, an elevated serum bilirubin level and dilated common duct on ultra- sonography suggest the diagnosis. Endoscopic retrograde cholangiopancreatography (ERCP) is the preferred method for stone extraction and should be performed in patients with a high likelihood of choledocholithiasis (Figure 37). In patients who are suspected of having common duct stones but have indeterminate findings on ultrasonography, mag- netic resonance cholangiopancreatography (MRCP) or endo- scopic ultrasonography should be performed to avoid ERCP risks. Cholecystectomy should be performed within 2 weeks of stone extraction. Cholangitis is infection of the biliary tree, usually in the setting of biliary stasis or obstruction. Symptoms include fever, jaundice, and right-upper-quadrant pain (Charcot triad). Cholangitis is potentially life-threatening; antibiotics targeting FIGURE 36. Gallbladder ultrasound consistent with acalculous cholecystitis gram-negative Enterobacteriaceae should be administered showing a thickened gallbladder wall (bottom), pericholecystic fluid (top), and an immediately. Common bile duct stones should be removed absence of gallstones or sludge. urgently with ERCP in patients with cholangitis, after which elective cholecystectomy should be performed during initial hospitalization to reduce the risk for complications. In patients e Acalculous cholecystitis typically occurs in critically ill who are not surgical candidates, endoscopic sphincterotomy patients and results from gallbladder ischemia, which can facilitate passage of additional common bile duct stones. can be complicated by enteric bacterial infection.

LONG LiveRRT & Pm a O-Fra 4.0 mH Common Bile Duct Stones — and Cholangitis Common bile duct stones are a leading cause of obstructive jaundice and pancreatitis. Although 20% of common duct stones pass spontaneously and less than 50% of patients develop symptoms, stone extraction should be offered to most patients. Symptoms of common bile duct stones include jaundice and abdominal pain due to obstruction of bile flow. Common duct stones may be visualized by transabdominal ultrasonography. In the absence of visualization, an elevated serum bilirubin level and dilated common duct on ultra- sonography suggest the diagnosis. Endoscopic retrograde cholangiopancreatography (ERCP) is the preferred method for stone extraction and should be performed in patients with a high likelihood of choledocholithiasis (Figure 37). In patients who are suspected of having common duct stones but have indeterminate findings on ultrasonography, mag- netic resonance cholangiopancreatography (MRCP) or endo- scopic ultrasonography should be performed to avoid ERCP risks. Cholecystectomy should be performed within 2 weeks of stone extraction. Cholangitis is infection of the biliary tree, usually in the setting of biliary stasis or obstruction. Symptoms include fever, jaundice, and right-upper-quadrant pain (Charcot triad). Cholangitis is potentially life-threatening; antibiotics targeting FIGURE 36. Gallbladder ultrasound consistent with acalculous cholecystitis gram-negative Enterobacteriaceae should be administered showing a thickened gallbladder wall (bottom), pericholecystic fluid (top), and an immediately. Common bile duct stones should be removed absence of gallstones or sludge. urgently with ERCP in patients with cholangitis, after which elective cholecystectomy should be performed during initial hospitalization to reduce the risk for complications. In patients e Acalculous cholecystitis typically occurs in critically ill who are not surgical candidates, endoscopic sphincterotomy patients and results from gallbladder ischemia, which can facilitate passage of additional common bile duct stones. can be complicated by enteric bacterial infection. e Inalert patients, the presentation is pain, similar to that seen in cholecystitis; in sedated or mechanically ventilated patients, it may present with leukocytosis, jaundice, and sepsis.

LONG LiveRRT & Pm a O-Fra 4.0 mH Common Bile Duct Stones — and Cholangitis Common bile duct stones are a leading cause of obstructive jaundice and pancreatitis. Although 20% of common duct stones pass spontaneously and less than 50% of patients develop symptoms, stone extraction should be offered to most patients. Symptoms of common bile duct stones include jaundice and abdominal pain due to obstruction of bile flow. Common duct stones may be visualized by transabdominal ultrasonography. In the absence of visualization, an elevated serum bilirubin level and dilated common duct on ultra- sonography suggest the diagnosis. Endoscopic retrograde cholangiopancreatography (ERCP) is the preferred method for stone extraction and should be performed in patients with a high likelihood of choledocholithiasis (Figure 37). In patients who are suspected of having common duct stones but have indeterminate findings on ultrasonography, mag- netic resonance cholangiopancreatography (MRCP) or endo- scopic ultrasonography should be performed to avoid ERCP risks. Cholecystectomy should be performed within 2 weeks of stone extraction. Cholangitis is infection of the biliary tree, usually in the setting of biliary stasis or obstruction. Symptoms include fever, jaundice, and right-upper-quadrant pain (Charcot triad). Cholangitis is potentially life-threatening; antibiotics targeting FIGURE 36. Gallbladder ultrasound consistent with acalculous cholecystitis gram-negative Enterobacteriaceae should be administered showing a thickened gallbladder wall (bottom), pericholecystic fluid (top), and an immediately. Common bile duct stones should be removed absence of gallstones or sludge. urgently with ERCP in patients with cholangitis, after which elective cholecystectomy should be performed during initial hospitalization to reduce the risk for complications. In patients e Acalculous cholecystitis typically occurs in critically ill who are not surgical candidates, endoscopic sphincterotomy patients and results from gallbladder ischemia, which can facilitate passage of additional common bile duct stones. can be complicated by enteric bacterial infection. e Inalert patients, the presentation is pain, similar to that seen in cholecystitis; in sedated or mechanically ventilated patients, it may present with leukocytosis, jaundice, and sepsis. Functional Gallbladder Disorder Functional gallbladder disorder should be considered in patients with biliary pain without gallstones or structural pathology. Other causes of upper abdominal discomfort, including peptic ulcer disease and angina, should be consid- ered. A gallbladder ejection fraction less than 40% as measured by cholecystokinin-stimulated cholescintigraphy supports the diagnosis but may not predict response to chol- ecystectomy. Reassurance and antispasmodic agents may be of benefit. If no other cause of pain is found, pain recurs, and the gallbladder ejection fraction is less than 40%, then cholecys- tectomy can be considered. In clinical practice, patients “

Functional Gallbladder Disorder Functional gallbladder disorder should be considered in patients with biliary pain without gallstones or structural pathology. Other causes of upper abdominal discomfort, including peptic ulcer disease and angina, should be consid- ered. A gallbladder ejection fraction less than 40% as measured by cholecystokinin-stimulated cholescintigraphy supports the diagnosis but may not predict response to chol- ecystectomy. Reassurance and antispasmodic agents may be of benefit. If no other cause of pain is found, pain recurs, and the gallbladder ejection fraction is less than 40%, then cholecys- tectomy can be considered. In clinical practice, patients “ who meet these criteria and undergo cholecystectomy may FIGURE 37. Choledocholithiasis is seen on endoscopic retrograde continue to have similar upper abdominal symptoms cholangiopancreatography, which shows an approximately 5 mm, round opacity in postoperatively. the distal common bile duct consistent with a stone. 73