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InternalMed_Harrison. and/or the dose of ribavirin to as high as 1600 mg daily (if tolerated or supplemented by erythropoietin) or by tailoring treatment based on viral response to prolong the duration of viral clearance before discontinuing therapy, i.e., extending therapy from 48 to 72 weeks for patients with genotype 1 and a slow virologic response (i.e., those whose HCV RNA has not fallen rapidly to undetectable levels within 4 weeks [absence of RVR]). Tailoring therapy based on the kinetics of HCV RNA reduction has also been applied to abbreviating the duration of therapy in patients with genotype 1 (and 4). The results of several clinical trials suggest that, in patients with genotype 1 (and 4) who have a 4-week RVR (which occurs in ≤20%), especially in the subset with low baseline HCV RNA, 24 weeks of therapy with PEG IFN and weight-based ribavirin suffices, yielding SVR rates of ~90% and comparable to those achieved in this cohort with 48 weeks of therapy. Although initial reports suggested that,


InternalMed_Harrison

InternalMed_Harrison. therapy with PEG IFN and weight-based ribavirin suffices, yielding SVR rates of ~90% and comparable to those achieved in this cohort with 48 weeks of therapy. Although initial reports suggested that, for patients with genotype 2 and (somewhat less so) genotype 3, in rapid virologic responders with undetectable HCV RNA at week 4, the total duration of therapy required to achieve an SVR could be as short as 12−16 weeks, a very sizable, definitive subsequent trial showed that relapse is increased if treatment duration is curtailed and that a full 24 weeks is superior for these genotypes (except for the minority with very low baseline levels of HCV RNA). Persons with chronic HCV infection have been shown to suffer increased liver-related mortality. On the other hand, successful antiviral therapy of chronic hepatitis C resulting in an SVR has been shown to improve survival (and to reduce the need for liver transplantation), to lower the risk of liver failure and liver-related death and


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InternalMed_Harrison. of chronic hepatitis C resulting in an SVR has been shown to improve survival (and to reduce the need for liver transplantation), to lower the risk of liver failure and liver-related death and all-cause deaths, to slow the progression of chronic hepatitis C, and to reverse fibrosis and even cirrhosis. Although successful treatment reduces mortality in cirrhotic patients (and those with advanced fibrosis) and reduces the likelihood of HCC, the risk of liver-related death and HCC persists, albeit at a much reduced level, necessitating continued clinical monitoring and cancer surveillance after SVR in cirrhotics. On the other hand, in the absence of an SVR, routine-dose/duration IFN-based therapy does not reduce the risk of HCC. Similarly, for nonresponders to PEG IFN–ribavirin therapy, three trials of long-term maintenance therapy with PEG IFN have shown no benefit in reducing the risk of histologic progression or clinical decompensation, including the development of HCC. For PEG


InternalMed_Harrison

InternalMed_Harrison. three trials of long-term maintenance therapy with PEG IFN have shown no benefit in reducing the risk of histologic progression or clinical decompensation, including the development of HCC. For PEG IFN–ribavirin nonresponders who have had a full, adequate course of therapy, the benefit of retreatment—with higher doses or a longer course of the original PEG IFN regimen or the alternative PEG IFN regimen or with a different type of IFN preparation (e.g., consensus IFN)—is marginal at best. Fortunately, such non-responders can now be retreated with protease inhibitor-based therapy (see following).


InternalMed_Harrison

InternalMed_Harrison. The HCV RNA genome encodes a single polyprotein, which is cleaved during and after translation by host and viral-encoded proteases. One protease involved in the cleavage of the viral polyprotein is an NS3-4A viral protein that has serine protease activity. Telaprevir and boceprevir are serine protease inhibitors that target NS3-4A. In 2011, telaprevir and boceprevir used in combination with PEG IFN and ribavirin were approved by the U.S. Food and Drug Administration (FDA) for the treatment of hepatitis C genotype 1 in adults with stable liver disease, both in patients who have not been treated before or who have failed previous treatment. Because the presently available HCV protease inhibitors have not been studied comprehensively in patients with genotypes other than 1, their use in these populations is not recommended.


InternalMed_Harrison

InternalMed_Harrison. Because resistance develops rapidly, both telaprevir and boceprevir must be used in combination with a PEG IFN and ribavirin-based regimen and should never be used alone. Ribavirin in particular appears to reduce relapse rates significantly in protease inhibitor– based regimens, such that those who cannot take or are intolerant to ribavirin are unlikely to benefit from the addition of these agents. All current telaprevir and boceprevir regimens consist of periods of triple therapy (protease inhibitor plus PEG IFN plus ribavirin) and periods of dual therapy (PEG IFN plus ribavirin). Telaprevir regimens begin with 12 weeks of triple therapy followed by dual therapy of a duration based on HCV RNA status at weeks 4 and 12 (“responseguided therapy”) and prior treatment status. Boceprevir-based regimens consist of a 4-week lead-in period of dual (PEG IFN–ribavirin) therapy followed by triple therapy and, in some instances, a further extension of dual therapy, with duration of


InternalMed_Harrison

InternalMed_Harrison. regimens consist of a 4-week lead-in period of dual (PEG IFN–ribavirin) therapy followed by triple therapy and, in some instances, a further extension of dual therapy, with duration of response-guided therapy based on HCV RNA status at weeks 4, 8, and 24 and prior treatment status (Table 362-7).


InternalMed_Harrison

InternalMed_Harrison. For patients with HCV genotype 1, protease inhibitors have significantly improved the frequency of RVRs and SVRs as compared to PEG IFN plus ribavirin alone. In treatment-naïve patients treated with telaprevir, an SVR was seen in up to 79% of patients who received 12 weeks of triple therapy followed by 12–36 weeks of dual therapy, and among those with EVRs (undetectable HCV RNA at weeks 4 and 12) and response-guided therapy stopped at week 24 (12 weeks of triple therapy, then 12 weeks of dual therapy), the rate of SVRs was 83–89% (92% in a subsequent study). In studies with boceprevir in treatment-naïve patients, SVRs were seen in 59–66% of patients, and among those with undetectable HCV RNA at 8 weeks, the SVR rate increased to 86–88%.


InternalMed_Harrison

InternalMed_Harrison. Protease inhibitors have also been studied in patients previously treated unsuccessfully with PEG IFN plus ribavirin. In studies with telaprevir, SVRs were seen in 83–88% of patients who had a previous relapse, 54–59% of partial responders (HCV RNA reduced by ≥2 log10 IU/mL but not to undetectable levels), and 29–33% of null responders (HCV RNA reduced by <2 log10 IU/mL). With boceprevir, SVRs occurred in 75% of prior relapsers and in 40–52% of previous partial responders; response rates in null responders are similar to those achieved with telaprevir-based therapy. In a substantial proportion of protease inhibitor nonresponders, resistance-associated variants can be identified, but these variants are not archived, and wild-type HCV reemerges in almost all cases within 1.5 to 2 years. SVRs to these protease inhibitors are highest in prior relapsers and


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InternalMed_Harrison. Detectable HCV RNA (with or without elevated ALT) Portal/bridging fibrosis or moderate to severe hepatitis on liver biopsy (the necessity of a pretreatment biopsy is no longer embraced universally) Indications for IFN/ribavirin-based therapy apply to adults as well as to children age 2–17, in whom treatment may be considered at reduced weight-based doses (see product inserts); protease inhibitors are not recommended for children age <18 years Relapsers, partial responders, or nonresponders after a previous course of standard IFN monotherapy or combination standard IFN/ribavirin therapy or PEG IFN/ ribavirin A course of PEG IFN/ribavirin plus protease inhibitor as below Genotypes 2, 3, 4


InternalMed_Harrison

InternalMed_Harrison. A course of PEG IFN/ribavirin plus protease inhibitor as below Genotypes 2, 3, 4 Relapsers after a previous course of standard IFN monotherapy or combination standard IFN/ribavirin therapy A course of PEG IFN plus ribavirin Nonresponders to a previous course of standard IFN monotherapy or combination standard IFN/ribavirin therapy A course of PEG IFN plus ribavirin—more likely to achieve a sustained virologic response in white patients without previous ribavirin therapy, with low baseline HCV RNA levels, with a ≥2-log10 reduction in HCV RNA during previous therapy, with genotypes 2 and 3, and without reduction in ribavirin dose Children (age <18 years)—protease inhibitors not recommended. Age >70 (in protease inhibitor trials, telaprevir trials included patients age 18–70; boceprevir trials included patients >18 years of age [no upper age cutoff ]) Mild hepatitis on liver biopsy Persons with severe renal insufficiency (require reduced doses of PEG IFN and ribavirin)


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InternalMed_Harrison. Cutaneous vasculitis and glomerulonephritis associated with chronic hepatitis C Decompensated cirrhosis (except, perhaps, in transplantation centers with experience in graded escalation, low-dose treatment to achieve undetectable HCV RNA prior to transplantation; results are mixed) Pregnancy (teratogenicity of ribavirin) Contraindications to use of antiviral medications PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN-α2b 1.5 μg/kg weekly plus weight-based ribavirin 800 mg/d (≤65 kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) Plus response-guided therapy with a protease inhibitor consisting of either: Boceprevir 800 mg three times daily with food started after a lead-in treatment of 4 weeks with PEG IFN–ribavirin • Patients with undetectable HCV RNA at 8 and 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, boceprevir) through week 28 (4 weeks of PEG


InternalMed_Harrison

InternalMed_Harrison. IFN–ribavirin then 24 weeks of triple-drug therapy). If HCV RNA is detectable at 4 weeks, continuing therapy through 48 weeks (4 weeks of PEG IFN–ribavirin then 44 weeks of triple-drug therapy) may increase the sustained response rate. • Patients with detectable HCV RNA at 8 weeks and undetectable at 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, boceprevir) through week 36 (4 weeks of PEG IFN–ribavirin then 32 weeks of triple-drug therapy) followed by a return to PEG IFN–ribavirin for 12 more weeks, for a total treatment duration of 48 weeks. • Patients with cirrhosis who are treatment-naive and have undetectable HCV RNA at weeks 8 and 24 should continue triple-drug therapy (PEG IFN, ribavirin, boceprevir) through 48 weeks (4 weeks of PEG IFN–ribavirin then 44 weeks of triple-drug therapy). • Stopping rules for futility: HCV RNA ≥100 IU/mL at week 12 or any detectable HCV RNA at week 24


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InternalMed_Harrison. • Stopping rules for futility: HCV RNA ≥100 IU/mL at week 12 or any detectable HCV RNA at week 24 Telaprevir 750 mg three times daily with fatty food started at the beginning of therapy without a PEG IFN–ribavirin lead-in with undetectable HCV RNA at 4 and 12 weeks should receive triple-drug therapy (PEG IFN, ribavirin, telaprevir) for 12 weeks then PEG IFN and ribavirin for another 12 weeks, for a total of 24 weeks. with detectable HCV RNA at 4 or 12 weeks and undetectable at 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, telaprevir) for 12 weeks, then PEG IFN–ribavirin for another 36 weeks, for a total treatment duration of 48 weeks. • Patients with cirrhosis who are treatment-naïve and have undetectable HCV RNA at 4 and 12 weeks should receive triple-drug therapy for 12 weeks then PEG IFN–ribavirin for another 36 weeks, for a total treatment duration of 48 weeks.


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InternalMed_Harrison. IFN–ribavirin for another 36 weeks, for a total treatment duration of 48 weeks. • Stopping rules for futility: HCV RNA >1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24


InternalMed_Harrison

InternalMed_Harrison. • Stopping rules for futility: HCV RNA >1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24 PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN-α2b 1.5 μg/kg weekly plus weight-based ribavirin 800 mg/d (≤65kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) Plus a protease inhibitor consisting of either: Response-guided therapy with boceprevir 800 mg three times daily with food started after a lead-in treatment of 4 weeks with PEG IFN–ribavirin • For prior relapsers and partial responders (HCV RNA reduction of ≥2 log10 during previous therapy), follow the response-guided algorithm below; for prior null responders (HCV RNA reduction <2 log10 during previous therapy), a full 48-week course of therapy (4-week PEG IFN–ribavirin lead-in, followed by 44 weeks of triple-drug therapy [PEG IFN, ribavirin, boceprevir]) is recommended.


InternalMed_Harrison

InternalMed_Harrison. • Patients with undetectable HCV RNA at 8 and 24 weeks should receive triple-drug therapy (PEG IFN, ribavirin, boceprevir) through week 36 (4 weeks of PEG IFN–ribavirin then 32 weeks of triple-drug therapy). If HCV RNA is detectable at 4 weeks, continuing therapy through 48 weeks (4 weeks of PEG IFN–ribavirin then 44 weeks of triple therapy) may increase the sustained response rate. • Patients with detectable HCV RNA at 8 weeks and undetectable at week 24 should receive triple-drug therapy (PEG IFN, ribavirin, boceprevir) through week 36 (4 weeks of PEG IFN–ribavirin then 32 weeks of triple-drug therapy), followed by a return to PEG IFN–ribavirin for 12 more weeks, for a total treatment duration of 48 weeks. with cirrhosis who are treatment-experienced and have undetectable HCV RNA at weeks 8 and 24 should continue triple-drug therapy (PEG IFN, ribavirin, boceprevir) through 48 weeks (4 weeks of PEG IFN–ribavirin then 44 weeks of triple-drug therapy).


InternalMed_Harrison

InternalMed_Harrison. rules for futility: HCV RNA ≥100 IU/mL at week 12 or any detectable HCV RNA at week 24 Telaprevir 750 mg three times daily with fatty food started at the beginning of therapy without a PEG IFN–ribavirin lead-in and without a response-guided approach, i.e., all patients receive a full 48-week course, independent of early responsiveness. prior relapsers, follow guidelines for treatment-naïve patients above. partial responders and null responders should receive triple-drug therapy (PEG IFN, ribavirin, telaprevir) for 12 weeks then PEG IFN and ribavirin for another 36 weeks, for a total of 48 weeks. • Stopping rules for futility: HCV RNA >1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24


InternalMed_Harrison

InternalMed_Harrison. • Stopping rules for futility: HCV RNA >1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24 HCV genotype 1 but protease inhibitors unavailable or contraindicated: 48 weeks of therapy PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN-α2b 1.5 μg/kg weekly plus weight-based ribavirin 800 mg/d (≤65 kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) HCV genotype 4: 48 weeks of PEG IFN–ribavirin therapy PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN-α2b 1.5 μg/kg weekly plus weight-based ribavirin 800 mg/d (≤65 kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) Treatment should be discontinued in patients who do not achieve an early virologic response at week 12. Patients who do achieve an early virologic response should be retested at week 24, and treatment should be discontinued if HCV RNA remains detectable.


InternalMed_Harrison

InternalMed_Harrison. Patients who do achieve an early virologic response should be retested at week 24, and treatment should be discontinued if HCV RNA remains detectable. HCV genotypes 2 and 3: 24 weeks of therapy PEG IFN-α2b 1.5 μg/kg weekly plus ribavirin 800 mg/d (for patients with genotype 3 who have advanced fibrosis and/or high-level HCV RNA, a full 48 weeks of therapy may be preferable)


InternalMed_Harrison

InternalMed_Harrison. For HCV/HIV co-infected patients: 48 weeks, regardless of genotype, of weekly PEG IFN-α2a (180 μg) or PEG IFN-α2b (1.5 μg/kg) plus a daily ribavirin dose of at least 600–800 mg, up to full weight-based 1000–1400 mg dosing if tolerated. Protease inhibitors may be used for genotype 1; however, because of potential drug-drug interactions between HCV protease inhibitors and HIV antiretroviral drugs, HCV protease inhibitors should be used cautiously in HCV/HIV co-infected patients. If protease inhibitors are used, a full 48-week course is recommended without response-guided therapy. For boceprevir, 4 weeks of PEG IFN–ribavirin lead-in, followed by 44 weeks of triple-drug therapy (PEG IFN, ribavirin, boceprevir). For telaprevir, 12 weeks of triple-drug therapy (PEG IFN, ribavirin, telaprevir), followed by 36 weeks of PEG IFN–ribavirin therapy. Stopping rules for futility are as noted above. Features Associated with Reduced Responsiveness


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InternalMed_Harrison. Single nucleotide polymorphism (SNP) T allele (as opposed to C allele) at IL28B locus Genotype 1a (compared to 1b) High-level HCV RNA (>800,000 IU/mL)b Advanced fibrosis (bridging fibrosis, cirrhosis) Long-duration disease Age >40b High HCV quasispecies diversity Immunosuppression African-American ethnicity Latino ethnicity Obesity Hepatic steatosis Insulin resistance, type 2 diabetes mellitusb Reduced adherence (lower drug doses and reduced duration of therapy) For boceprevir, <1 log10 reduction in HCV RNA during 4-week PEG IFN–ribavirin lead-in For protease inhibitor therapy, absence of extended rapid virologic response (eRVR), i.e., detectable HCV RNA, at weeks 4 and 12 for telaprevir; at weeks 8 and 24 for boceprevir aAs this chapter was going to press, two additional drugs were approved for hepatitis C, simeprevir and sofosbuvir. Rapidly evolving new recommendations are supplanting the recommendations in this table; for up-to-date treatment recommendations, please see


InternalMed_Harrison

InternalMed_Harrison. were approved for hepatitis C, simeprevir and sofosbuvir. Rapidly evolving new recommendations are supplanting the recommendations in this table; for up-to-date treatment recommendations, please see www.hcvguidelines.org. bLess influential in patients treated with protease inhibitors.


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InternalMed_Harrison. Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN, interferon; PEG IFN, pegylated interferon; IU, international units (1 IU/mL is equivalent to ~2.5 copies/mL).


InternalMed_Harrison

InternalMed_Harrison. treatment-naïve patients (white > black ethnicity), lower in prior PEG IFN–ribavirin lead-in therapy. Age and HCV RNA level are less partial responders, lower still in prior null responders, and lowest in influential and insulin resistance is noninfluential on response to cirrhotic prior null responders (Fig. 362-3). Responses to protease these antiviral agents. inhibitor triple-drug regimens are higher in patients with IL28B C Both protease inhibitors have potential toxicities. Telaprevir is than non-C genotypes, HCV genotype 1b than genotype 1a, less associated with a severe, generalized (trunk and extremities), often advanced than more advanced fibrosis stage, whites than blacks, confluent, maculopapular, pruritic rash in ~6% of treated patients. lower body mass index (BMI) than elevated BMI, and, for boceprevir, Other common side effects include pruritus, rectal burning, nausea, achievement of a >1 log10 HCV RNA reduction during 4 weeks of diarrhea, fatigue, and anemia, which may


InternalMed_Harrison

InternalMed_Harrison. BMI, and, for boceprevir, Other common side effects include pruritus, rectal burning, nausea, achievement of a >1 log10 HCV RNA reduction during 4 weeks of diarrhea, fatigue, and anemia, which may be relatively refractory, % with sustained virologic response


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InternalMed_Harrison. FIGURE 362-3 Maximal efficacy (sustained virologic responses, SVR) of telaprevir (blue bars) and boceprevir (yellow bars) reported in phase III clinical trials. (Figure created using data from Bacon BR et al: N Engl J Med 364:1207, 2011; Jacobson IM et al: N Engl J Med 364:2405, 2011; Poordad F et al: N Engl J Med 364:1195, 2011; Zeuzem S et al: N Engl J Med 364:2417, 2011; Vierling JM et al: Hepatology 54 [Suppl 1]:796A-797A, 2011; Ghany MG et al: Hepatology 54:1433, 2011.) occasionally requiring transfusion. Complete blood counts should be obtained at baseline and then at 2, 4, 8, and 12 weeks after starting telaprevir. Anemia can occur in half of boceprevir-treated patients, as can neutropenia in up to 30% and thrombocytopenia in 3–4%. Complete blood counts should be obtained at baseline and then at 4, 8, and 12 weeks after starting boceprevir. Other side effects of boceprevir include fatigue, nausea, headache, dysgeusia (altered or unpleasant taste), dry mouth, vomiting, and


InternalMed_Harrison

InternalMed_Harrison. and then at 4, 8, and 12 weeks after starting boceprevir. Other side effects of boceprevir include fatigue, nausea, headache, dysgeusia (altered or unpleasant taste), dry mouth, vomiting, and diarrhea.


InternalMed_Harrison

InternalMed_Harrison. Use of protease inhibitors is further complicated by numerous drug-drug interactions. As telaprevir and boceprevir are both eliminated by and inhibit CYP3A4, these agents should not be administered with other medications that induce CYP3A4 or are dependent on CYP3A4 for elimination. Care should be taken to examine for any potential interactions between protease inhibitors and other medications the patient may be taking, because serious adverse events can occur. A convenient website is available to check for such drug-drug interactions (www.hep-druginteractions.org).


InternalMed_Harrison

InternalMed_Harrison. Prior to therapy, HCV genotype should be determined, because the genotype dictates the duration of therapy and potentially the agents to be used. PEG IFN plus ribavirin represents the foundation of treatment for all HCV genotypes; patients infected with genotype 1 should also receive a protease inhibitor (telaprevir or boceprevir) when these are available and not contraindicated (Table 362-7). For chronic HCV genotype 1 infection, the AASLD and EASL published treatment guidelines in 2011 reflecting FDA-approved indications for the new protease inhibitors, and in 2012, United Kingdom and French consensus guidelines were published. For treatment-naïve patients and prior relapsers, response-guided therapy with telaprevir or boceprevir is recommended. For telaprevir, the regimen consists of 12 weeks of triple therapy, followed by 12 or 36 weeks of PEG IFN–ribavirin consolidation, depending on whether extended RVR milestones (HCV RNA undetectable at weeks 4 and 12) are met.


InternalMed_Harrison

InternalMed_Harrison. *As this chapter was going to press, two additional antiviral drugs, a second-generation protease inhibitor simeprevir and nucleoside analogue polymerase inhibitor sofosbuvir were approved for the treatment of hepatitis C. Simerprevir, which is effective for genotype 1, must be administered, like first-generation protease inhibitors, for 12 weeks with PEG IFN and ribavirin, followed by another 12 weeks of PEG IFN and ribavirin (no response-guided therapy). Sofosbuvir, the more convenient and broadly applicable of the two new drugs, must be administered with PEG IFN and ribavirin but for only 12 weeks in patients with genotyes 1, 4-6; for patients with genotypes 2 and 3, PEG IFN is not required. Sofosbuvir plus ribavirin are administered for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Antiviral therapy is evolving very rapidly; by the end of 2014, all-oral, interferon-free combinations (e.g., sofosbuvir plus the NS5a inhibitor ledipasvir) will supplant earlier treatment


InternalMed_Harrison

InternalMed_Harrison. 3. Antiviral therapy is evolving very rapidly; by the end of 2014, all-oral, interferon-free combinations (e.g., sofosbuvir plus the NS5a inhibitor ledipasvir) will supplant earlier treatment regimens. For updated treatment recommendations, please consult www.hcvguidelines.org.


InternalMed_Harrison

InternalMed_Harrison. For boceprevir, the regimen consists of a 4-week PEG IFN–ribavirin 2047 lead-in period, followed by 24–32 weeks of triple-drug therapy, depending on whether HCV RNA milestones (undetectable at weeks 8 and 24) are met; if HCV RNA is detectable at week 8 but undetectable at week 24, after 36 weeks of therapy (4-week PEG IFN–ribavirin lead-in plus 32 weeks of triple-drug therapy), an additional 12 weeks of PEG IFN–ribavirin consolidation is recommended. For prior partial and null responders, a full 48-week course of telaprevir (no lead-in period, no response-guided therapy) is recommended; for boceprevir, a 4-week PEG IFN–ribavirin lead-in period is followed by response-guided therapy (32 weeks of triple-drug therapy if HCV RNA is undetectable at weeks 8 and 24 or, if HCV RNA is still detectable at week 8 [but undetectable at week 24], 32 weeks of triple-drug therapy followed by 12 weeks of PEG IFN–ribavirin consolidation). For cirrhotic patients (and for any boceprevir-treated patient


InternalMed_Harrison

InternalMed_Harrison. at week 8 [but undetectable at week 24], 32 weeks of triple-drug therapy followed by 12 weeks of PEG IFN–ribavirin consolidation). For cirrhotic patients (and for any boceprevir-treated patient whose HCV RNA does not fall by >1 log10 by week 4), a full 48-week course without response-guided therapy should be considered.


InternalMed_Harrison

InternalMed_Harrison. Monitoring of HCV plasma RNA is crucial in assessing response to therapy. The goal of treatment is to eradicate HCV RNA, which is predicted by the absence of HCV RNA by PCR 6 months after stopping treatment (SVR). When therapy relied on PEG IFN and ribavirin, failure to achieve a 2-log10 drop in HCV RNA by week 12 of therapy (EVR) rendered it unlikely that further therapy would result in an SVR. When PEG IFN and ribavirin are part of a protease inhibitor regimen, HCV RNA should be measured at baseline and at weeks 4, 8 (for boceprevir), 12, and 24 to assess response to treatment and to aid in decisions regarding treatment duration (response-guided therapy), as well as 12 and 24 weeks after therapy. Stopping rules are important to prevent the emergence of resistance; if HCV RNA is >1000 IU/ mL at 4 or 12 weeks of telaprevir (or still detectable at week 24), or if HCV RNA is ≥100 IU/mL at week 12 of boceprevir (or detectable at week 24), all treatment should be stopped.


InternalMed_Harrison

InternalMed_Harrison. Patients with chronic hepatitis C who have detectable HCV RNA in serum, whether or not aminotransferase levels are increased, and chronic hepatitis of at least moderate grade and stage (portal or bridging fibrosis) are candidates for antiviral therapy with PEG IFN plus ribavirin. Most authorities recommend 800 mg of ribavirin for patients with genotypes 2 and 3 for both types of PEG IFN and weight-based 1000−1200 mg (when used with PEG IFN-α2a) or 800−1400 mg (when used with PEG IFN-α2b) ribavirin for patients with genotype 1 (and 4), unless ribavirin is contraindicated (Table 362-7). These PEG IFN and ribavirin doses are used with protease inhibitors for patients with genotype 1 (Table 362-7). Although patients with persistently normal ALT activity tend to progress histologically very slowly or not at all, they respond to antiviral therapy just as well as do patients with elevated ALT levels; therefore, although observation without therapy is an option, such patients are potential


InternalMed_Harrison

InternalMed_Harrison. slowly or not at all, they respond to antiviral therapy just as well as do patients with elevated ALT levels; therefore, although observation without therapy is an option, such patients are potential candidates for antiviral therapy. As noted above, therapy with IFN has been shown to improve survival and complication-free survival and to slow progression of (and to reverse) fibrosis.


InternalMed_Harrison

InternalMed_Harrison. HCV genotype determines the duration of PEG IFN and ribavirin therapy: 24 weeks for those with genotypes 2 and 3 and 48 weeks for patients with genotypes 4 and 1 (in patients for whom protease inhibitors are not available or contraindicated). For patients with genotype 4, treatment should be discontinued in patients who do not achieve an EVR at week 12. For patients with genotypes 2 and 3, a full, 24-week course is most effective, although the duration may be reduced to 12−16 weeks for patients with genotype 2, a low baseline level of viremia, and an RVR, especially to be considered for patients who tolerate therapy poorly. Also, consideration should be given to increasing the duration of therapy to 48 weeks for patients with genotype 3 who have advanced fibrosis and/or a high baseline level of viremia. As noted above, the absence of a 2-log10 drop in HCV RNA at week 12 (EVR) weighs heavily against the likelihood of an SVR; therefore, measuring HCV RNA at 12 weeks is recommended


InternalMed_Harrison

InternalMed_Harrison. level of viremia. As noted above, the absence of a 2-log10 drop in HCV RNA at week 12 (EVR) weighs heavily against the likelihood of an SVR; therefore, measuring HCV RNA at 12 weeks is recommended routinely (Fig. 362-2), and therapy can be discontinued if an EVR is not achieved. Among patients with genotype 4 who achieve an 2048 EVR (≥2-log10 HCV RNA reduction) but in whom HCV RNA remains detectable at week 24, an SVR is unlikely, and therapy can be discontinued. Although response rates are lower in patients with certain pretreatment variables, selection for treatment should not be based on symptoms, genotype, HCV RNA level, mode of acquisition of hepatitis C, or advanced hepatic fibrosis. Patients with cirrhosis can respond and should not be excluded as candidates for therapy. For patients being treated with telaprevir and boceprevir, treating physicians should explain the negative impact of non-C IL28B genotype and advanced fibrosis on outcome. Patients who have relapsed after, or


InternalMed_Harrison

InternalMed_Harrison. being treated with telaprevir and boceprevir, treating physicians should explain the negative impact of non-C IL28B genotype and advanced fibrosis on outcome. Patients who have relapsed after, or failed to respond to (Fig. 362-2), a course of IFN monotherapy are potential candidates for retreatment with PEG IFN plus ribavirin (i.e., a more effective treatment regimen is required), and this approach remains current for patients with genotypes 2, 3, or 4; however, for patients with genotype 1, combination protease inhibitor/PEG IFN/ribavirin therapy is indicated. For patients with genotypes 2, 3, or 4 who were nonresponders to a prior course of IFN monotherapy, retreatment with IFN monotherapy or combination IFN plus ribavirin therapy is unlikely to achieve an SVR; however, a trial of combination PEG IFN plus ribavirin may be worthwhile, although an SVR is the outcome in <15−20% of patients. SVRs to retreatment of nonresponders are more frequent in those who had never received ribavirin


InternalMed_Harrison

InternalMed_Harrison. PEG IFN plus ribavirin may be worthwhile, although an SVR is the outcome in <15−20% of patients. SVRs to retreatment of nonresponders are more frequent in those who had never received ribavirin in the past, those with genotypes 2 and 3, those with low pretreatment HCV RNA levels, and noncirrhotics, but less frequent in African Americans, those who failed to achieve a substantial reduction in HCV RNA during their previous course of therapy (null responders, Fig. 362-2), and those who required ribavirin dose reductions. Potential approaches to improving responsiveness to PEG IFN–ribavirin in prior nonresponders include longer duration of treatment; higher doses of PEG IFN, ribavirin, or both; and switching to a different IFN preparation; however, as noted above, none of these approaches achieves more than a marginal benefit. Treatment with a protease inhibitor–based regimen should be pursued in patients with genotype 1 who have relapsed after or not responded to prior treatment with IFN


InternalMed_Harrison

InternalMed_Harrison. more than a marginal benefit. Treatment with a protease inhibitor–based regimen should be pursued in patients with genotype 1 who have relapsed after or not responded to prior treatment with IFN monotherapy or PEG IFN plus ribavirin, unless these protease inhibitors are not available or contraindicated (Table 362-7). Early PEG IFN treatment is indicated for persons with acute hepatitis C; ribavirin, which is used frequently in such instances, has not been shown to improve efficacy over that of PEG IFN alone, and the new protease inhibitors have not been approved for acute hepatitis C (Chap. 360). In patients with biochemically and histologically mild chronic hepatitis C, the rate of progression is slow, and monitoring without therapy is an option; however, such patients respond just as well to combination PEG IFN plus ribavirin therapy or triple-drug, protease-based therapy (for genotype 1) as those with elevated ALT and more histologically severe hepatitis. Therefore, therapy for


InternalMed_Harrison

InternalMed_Harrison. well to combination PEG IFN plus ribavirin therapy or triple-drug, protease-based therapy (for genotype 1) as those with elevated ALT and more histologically severe hepatitis. Therefore, therapy for these patients should be considered and the decision made based on such factors as patient motivation, genotype, stage of fibrosis, age, and comorbid conditions. A pretreatment liver biopsy to assess histologic grade and stage provides substantial information about progression of hepatitis C in the past, has prognostic value for future progression, and can identify such histologic factors as steatosis and stage of fibrosis, which can influence responsiveness to therapy. As therapy has improved for patients with a broad range of histologic severity, and as noninvasive laboratory markers and imaging correlates of fibrosis have gained popularity, some authorities, especially in Europe, place less value on, and do not recommend, pretreatment liver biopsies. On the other hand, serum markers of


InternalMed_Harrison

InternalMed_Harrison. correlates of fibrosis have gained popularity, some authorities, especially in Europe, place less value on, and do not recommend, pretreatment liver biopsies. On the other hand, serum markers of fibrosis are not considered sufficiently accurate, and histologic findings provide important prognostic information to physician and patient. Therefore, although the contemporary role of a pretreatment liver biopsy commands less of a consensus, a pretreatment liver biopsy still provides useful information and should be considered. Patients with compensated cirrhosis can respond to therapy, although their likelihood of a sustained response is lower than in noncirrhotics; moreover, survival has been shown to improve after successful antiviral therapy in cirrhotics. Similarly, although several retrospective studies have suggested that antiviral therapy in cirrhotics with chronic hepatitis C, independent of treatment outcome per se, reduces the frequency of HCC, less advanced disease in the


InternalMed_Harrison

InternalMed_Harrison. retrospective studies have suggested that antiviral therapy in cirrhotics with chronic hepatitis C, independent of treatment outcome per se, reduces the frequency of HCC, less advanced disease in the treated cirrhotics, not treatment itself (i.e., lead-time bias), may have accounted for the reduced frequency of HCC observed in the treated cohorts in these reports; prospective studies to address this question have failed to demonstrate benefit, unless an SVR is achieved. Patients with decompensated cirrhosis are not candidates for IFN-based antiviral therapy but should be referred for liver transplantation. Some liver transplantation centers have evaluated progressively escalated, low-dose antiviral therapy in an attempt to eradicate hepatitis C viremia prior to transplantation; however, such therapy has been shown to reduce but not to prevent the risk of HCV reinfection after transplantation. After liver transplantation for end-stage liver disease caused by hepatitis C, recurrent


InternalMed_Harrison

InternalMed_Harrison. such therapy has been shown to reduce but not to prevent the risk of HCV reinfection after transplantation. After liver transplantation for end-stage liver disease caused by hepatitis C, recurrent hepatitis C is the rule, and the pace of disease progression is more accelerated than in immunocompetent patients (Chap. 368). Current therapy with PEG IFN and ribavirin after liver transplantation is unsatisfactory in most patients, but attempts to minimize immunosuppression are beneficial. Early experience with protease inhibitor–based therapy is encouraging, but inhibition of CYP3A4 by protease inhibitors can lead to markedly increased levels of immunosuppressive calcineurin inhibitors (especially tacrolimus), which requires intensive monitoring and can be very challenging. The cutaneous and renal vasculitis of HCV-associated essential mixed cryoglobulinemia (Chap. 360) may respond to antiviral therapy, but sustained responses are rare after discontinuation of therapy; therefore,


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InternalMed_Harrison. and renal vasculitis of HCV-associated essential mixed cryoglobulinemia (Chap. 360) may respond to antiviral therapy, but sustained responses are rare after discontinuation of therapy; therefore, prolonged, perhaps indefinite, therapy (as reported with IFN-based therapy) is recommended in this group (no indication for prolonged protease inhibitor therapy exists currently). Anecdotal reports suggest that antiviral therapy may be effective in porphyria cutanea tarda or lichen planus associated with hepatitis C.


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InternalMed_Harrison. In patients with HCV/HIV co-infection, hepatitis C is more progressive and severe than in HCV-monoinfected patients. Although patients with HCV/HIV co-infection respond to antiviral therapy for hepatitis C, they do not respond as well as patients with HCV infection alone. Four large national and international trials of antiviral therapy among patients with HCV/HIV co-infection have shown that PEG IFN (both α2a and α2b) plus ribavirin (daily doses ranging from flat-dosed 600−800 mg to weight-based 1000/1200 mg) is superior to standard IFN regimens; however, SVR rates were lower than in HCV-monoinfected patients, ranging from 14 to 38% for patients with genotypes 1 and 4 and from 44 to 73% for patients with genotypes 2 and 3. In the three largest trials, all patients, including those with genotypes 2 and 3, were treated for a full 48 weeks. In addition, tolerability of therapy was lower than in HCV-monoinfected patients; therapy was discontinued because of side effects in 12−39% of


InternalMed_Harrison

InternalMed_Harrison. genotypes 2 and 3, were treated for a full 48 weeks. In addition, tolerability of therapy was lower than in HCV-monoinfected patients; therapy was discontinued because of side effects in 12−39% of patients in these clinical trials. Based on these trials, weekly PEG IFN plus daily ribavirin at a daily dose of at least 600−800 mg, up to full weight-based doses, at doses recommended for HCV-monoinfected patients, if tolerated, is recommended for a full 48 weeks, regardless of genotype. An alternative recommendation for ribavirin doses was issued by a European Consensus Conference and consisted of standard, weight-based 1000−1200 mg for genotypes 1 and 4, but 800 mg for genotypes 2 and 3. A head-to-head trial of combination PEG IFN–ribavirin therapy in HCV/HIV co-infection demonstrated statistically indistinguishable efficacy of the two types of PEG IFN, despite a small advantage for PEG IFN-α2a: For PEG IFN-α2b and -α2a, SVRs occurred in 28% versus 32%, respectively, of patients with


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InternalMed_Harrison. indistinguishable efficacy of the two types of PEG IFN, despite a small advantage for PEG IFN-α2a: For PEG IFN-α2b and -α2a, SVRs occurred in 28% versus 32%, respectively, of patients with genotypes 1 and 4 and in 62% versus 71%, respectively, of patients with genotypes 2 and 3.


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InternalMed_Harrison. Although data are limited and recommendations pending, protease inhibitors may be used for genotype 1; however, because of potential drug-drug interactions between HCV protease inhibitors and HIV antiretroviral drugs (especially in ritonavir-boosted HIV protease inhibitors), HCV protease inhibitors should be used cautiously in HCV-HIV co-infected patients. If protease inhibitors are used, a full 48-week course is recommended without response-guided therapy: for boceprevir, 4 weeks of PEG IFN–ribavirin lead-in, followed by 44 weeks of triple-drug therapy (PEG IFN, ribavirin, boceprevir), and for telaprevir, 12 weeks of triple-drug therapy (PEG IFN, ribavirin, telaprevir), followed by 36 weeks of PEG IFN–ribavirin therapy. In preliminary trials among HIV-HCV co-infected patients, telaprevirbased triple-drug therapy (independent of whether they were receiving antiretroviral therapy [no antiretroviral drugs, efavirenztenofovir-emtricitabine, or ritonavir-boosted


InternalMed_Harrison

InternalMed_Harrison. patients, telaprevirbased triple-drug therapy (independent of whether they were receiving antiretroviral therapy [no antiretroviral drugs, efavirenztenofovir-emtricitabine, or ritonavir-boosted atazanavir-tenofoviremtricitabine or lamivudine]) resulted in an SVR in 28 of 38 patients (74%), compared with 10 of 22 control patients (45%) treated with PEG IFN–ribavirin (60 study subjects); boceprevir-based triple-drug therapy (all were also receiving antiretroviral therapy) resulted in an SVR in 40 of 64 patients (63%), compared with 10 of 34 control patients (29%) treated with PEG IFN–ribavirin (98 study subjects). Thus, for the prior standard of care, PEG IFN plus ribavirin, although the likelihood of an SVR is lower for HIV-HCV co-infected patients than for HCV-monoinfected patients, for protease inhibitor–based regimens, rates of SVR are comparable in HIV-HCV co-infected and HCV-monoinfected patients.


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InternalMed_Harrison. In HCV/HIV-infected patients, ribavirin can potentiate the toxicity of didanosine (e.g., lactic acidosis) and the lipoatrophy of stavudine, and zidovudine can exacerbate ribavirin-associated hemolytic anemia; therefore, these drug combinations should be avoided.


InternalMed_Harrison

InternalMed_Harrison. Patients with a history of injection drug use and alcoholism can be treated successfully for chronic hepatitis C, preferably in conjunction with drug and alcohol treatment programs. Because ribavirin is excreted renally, patients with end-stage renal disease, including those undergoing dialysis (which does not clear ribavirin), are not ideal candidates for ribavirin therapy. Rare reports suggest that reduced-dose ribavirin can be used, but the frequency of anemia is very high, and data on efficacy are limited. If patients with renal failure (glomerular filtration rate <60 mL/min) are treated, the PEG IFNα2a dose should be reduced from 180 to 135 μg weekly and the PEG IFN-α2b dose reduced from 1.5 to 1 μg/kg weekly; similarly, the daily ribavirin dose in this population should be reduced to 200−800 mg (but not used or used cautiously at very low doses) if hemodialysis is required. Neither the optimal regimen nor the efficacy of therapy is well established in this population.


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InternalMed_Harrison. To date, attempts to develop better-tolerated ribavirin successors or improved types of IFN-α or longer acting IFNs than PEG IFN have not been successful. The demonstration that responsiveness to antiviral therapy is influenced by genetic variation in IL28B, which codes for IFN-λ (as noted above), raises the possibility that IFN-λ might be an effective or even more effective IFN for treating hepatitis C; early trials are in progress, but elevations of aminotransferase levels in treated subjects have raised concerns and delayed development. Beyond telaprevir and boceprevir, other direct antivirals that target HCV polymerase, protease, or NS5A (a membrane phosphoprotein component of the viral replication complex) are being investigated, as well as agents that can target host-encoded proteins. Among the novel antivirals are drugs with improved pharmacokinetic and resistance profiles, less treatment complexity, pangenotypic activity, fewer side effects, and fewer drug-drug interactions.*


InternalMed_Harrison

InternalMed_Harrison. Among the novel antivirals are drugs with improved pharmacokinetic and resistance profiles, less treatment complexity, pangenotypic activity, fewer side effects, and fewer drug-drug interactions.* The pace of successful trials of all-oral regimens has accelerated. All-oral combinations of a second-generation protease inhibitor (asunaprevir) plus an NS5A inhibitor (daclatasvir); of a uridine nucleoside polymerase inhibitor (sofosbuvir)* plus ribavirin; of a polymerase inhibitor (sofosbuvir) plus an NS5A inhibitor (ledipasvir or daclatasvir) and ribavirin; and of combinations of a ritonavirboosted protease inhibitor (ABT-450) plus a nonnucleoside polymerase inhibitor (ABT-333) plus an NS5A inhibitor (ABT-267) with or without ribavirin have been studied in clinical trials. Several of these drug combinations have achieved SVR rates exceeding 90%, even approaching 100%, for both treatment-naïve and treatment-experienced patients (including patients who failed to respond to first-generation


InternalMed_Harrison

InternalMed_Harrison. combinations have achieved SVR rates exceeding 90%, even approaching 100%, for both treatment-naïve and treatment-experienced patients (including patients who failed to respond to first-generation protease inhibitors), across all HCV genotypes and independent of host IL28B genotype, and with treatment durations of 12–24 weeks or even shorter (8 weeks). Potentially, as early as 2014 or 2015, such combinations of direct antiviral agents will be used in drug cocktails that may replace IFN-based regimens 2049 entirely.


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InternalMed_Harrison. Less advanced is development of inhibitors of host proteins, such as oral, nonimmunosuppressive inhibitors of cyclophilin A (which interacts with NS5A during HCV replication) and subcutaneous antisense antagonists of host liver-expressed micro-RNA-122 (which promotes HCV replication). Given the accelerated progress of all-oral, short-treatment-duration, high-efficacy, direct-acting antivirals, these alternative approaches may not be practical or competitive.


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InternalMed_Harrison. Autoimmune hepatitis is a chronic disorder characterized by continuing hepatocellular necrosis and inflammation, usually with fibrosis, which can progress to cirrhosis and liver failure. When fulfilling criteria of severity, this type of chronic hepatitis, when untreated, may have a 6-month mortality of as high as 40%. Based on contemporary estimates of the natural history of autoimmune hepatitis, the 10-year survival is 80−98% for treated and 67% for untreated patients. The prominence of extrahepatic features of autoimmunity and seroimmunologic abnormalities in this disorder supports an autoimmune process in its pathogenesis; this concept is reflected in the prior labels lupoid and plasma cell hepatitis. Autoantibodies and other typical features of autoimmunity, however, do not occur in all cases; among the broader categories of “idiopathic” or cryptogenic chronic hepatitis, many, perhaps the majority, are probably autoimmune in origin. Cases in which hepatotropic viruses,


InternalMed_Harrison

InternalMed_Harrison. occur in all cases; among the broader categories of “idiopathic” or cryptogenic chronic hepatitis, many, perhaps the majority, are probably autoimmune in origin. Cases in which hepatotropic viruses, metabolic/genetic derangements (including nonalcoholic fatty liver disease), and hepatotoxic drugs have been excluded represent a spectrum of heterogeneous liver disorders of unknown cause, a proportion of which are most likely autoimmune hepatitis.


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InternalMed_Harrison. The weight of evidence suggests that the progressive liver injury in patients with autoimmune hepatitis is the result of a cell-mediated immunologic attack directed against liver cells. In all likelihood, predisposition to autoimmunity is inherited, whereas the liver specificity of this injury is triggered by environmental (e.g., chemical, drug [e.g., minocycline], or viral) factors. For example, patients have been described in whom apparently self-limited cases of acute hepatitis A, B, or C led to autoimmune hepatitis, presumably because of genetic susceptibility or predisposition. Evidence to support an autoimmune pathogenesis in this type of hepatitis includes the following: (1) In the liver, the histopathologic lesions are composed predominantly of cytotoxic T cells and plasma cells; (2) circulating autoantibodies (nuclear, smooth muscle, thyroid, etc.; see below), rheumatoid factor, and hyperglobulinemia are common; (3) other autoimmune disorders— such as thyroiditis, rheumatoid


InternalMed_Harrison

InternalMed_Harrison. (2) circulating autoantibodies (nuclear, smooth muscle, thyroid, etc.; see below), rheumatoid factor, and hyperglobulinemia are common; (3) other autoimmune disorders— such as thyroiditis, rheumatoid arthritis, autoimmune hemolytic anemia, ulcerative colitis, membranoproliferative glomerulonephritis, juvenile diabetes mellitus, celiac disease, and Sjögren’s syndrome— occur with increased frequency in patients and in their relatives who have autoimmune hepatitis; (4) histocompatibility haplotypes associated with autoimmune diseases, such as HLA-B1, -B8, -DR3, and -DR4 as well as extended haplotype DRB1*0301 and DRB1*0401 alleles, are common in patients with autoimmune hepatitis; and (5) this type of chronic hepatitis is responsive to glucocorticoid/immunosuppressive therapy, effective in a variety of autoimmune disorders.


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InternalMed_Harrison. Cellular immune mechanisms appear to be important in the pathogenesis of autoimmune hepatitis. In vitro studies have suggested that in patients with this disorder, CD4+ T lymphocytes are capable of becoming sensitized to hepatocyte membrane proteins and of destroying liver cells. Molecular mimicry by cross-reacting antigens that contain epitopes similar to liver antigens is postulated to activate these T cells, which infiltrate, and result in injury to, the liver. Abnormalities of immunoregulatory control over cytotoxic lymphocytes (impaired regulatory CD4+CD25+ T cell influences) may play a role as well. Studies of genetic predisposition to autoimmune hepatitis demonstrate that certain haplotypes are associated with the disorder, as enumerated above, 2050 as are polymorphisms in cytotoxic T lymphocyte antigens (CTLA-4) and tumor necrosis factor α (TNFA*2). The precise triggering factors, genetic influences, and cytotoxic and immunoregulatory mechanisms involved in this type of liver


InternalMed_Harrison

InternalMed_Harrison. T lymphocyte antigens (CTLA-4) and tumor necrosis factor α (TNFA*2). The precise triggering factors, genetic influences, and cytotoxic and immunoregulatory mechanisms involved in this type of liver injury remain incompletely defined. Intriguing clues into the pathogenesis of autoimmune hepatitis come from the observation that circulating autoantibodies are prevalent in patients with this disorder. Among the autoantibodies described in these patients are antibodies to nuclei (so-called antinuclear antibodies [ANAs], primarily in a homogeneous pattern) and smooth muscle (so-called anti-smooth-muscle antibodies, directed at actin, vimentin, and skeletin), antibodies to F-actin, antibodies to liver-kidney microsomes (anti-LKM, see below), antibodies to “soluble liver antigen” (directed against a uracil-guanine-adenine transfer RNA suppressor protein), antibodies to α-actinin, and antibodies to the liver-specific asialoglycoprotein receptor (or “hepatic lectin”) and other hepatocyte


InternalMed_Harrison

InternalMed_Harrison. against a uracil-guanine-adenine transfer RNA suppressor protein), antibodies to α-actinin, and antibodies to the liver-specific asialoglycoprotein receptor (or “hepatic lectin”) and other hepatocyte membrane proteins. Although some of these provide helpful diagnostic markers, their involvement in the pathogenesis of autoimmune hepatitis has not been established. Humoral immune mechanisms have been shown to play a role in the extrahepatic manifestations of autoimmune and idiopathic hepatitis. Arthralgias, arthritis, cutaneous vasculitis, and glomerulonephritis occurring in patients with autoimmune hepatitis appear to be mediated by the deposition of circulating immune complexes in affected tissue vessels, followed by complement activation, inflammation, and tissue injury. While specific viral antigen-antibody complexes can be identified in acute and chronic viral hepatitis, the nature of the immune complexes in autoimmune hepatitis has not been defined.


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InternalMed_Harrison. Many of the clinical features of autoimmune hepatitis are similar to those described for chronic viral hepatitis. The onset of disease may be insidious or abrupt; the disease may present initially like, and be confused with, acute viral hepatitis; a history of recurrent bouts of what had been labeled acute hepatitis is not uncommon. In approximately a quarter of patients, the diagnosis is made in the absence of symptoms, based on abnormal liver laboratory tests. A subset of patients with autoimmune hepatitis has distinct features. Such patients are predominantly young to middle-aged women with marked hyperglobulinemia and high-titer circulating ANAs. This is the group with positive lupus erythematosus (LE) preparations (initially labeled “lupoid “ hepatitis) in whom other autoimmune features are common. Fatigue, malaise, anorexia, amenorrhea, acne, arthralgias, and jaundice are common. Occasionally, arthritis, maculopapular eruptions (including cutaneous vasculitis), erythema nodosum,


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InternalMed_Harrison. are common. Fatigue, malaise, anorexia, amenorrhea, acne, arthralgias, and jaundice are common. Occasionally, arthritis, maculopapular eruptions (including cutaneous vasculitis), erythema nodosum, colitis, pleurisy, pericarditis, anemia, azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia) occur. In some patients, complications of cirrhosis, such as ascites and edema (associated with portal hypertension and hypoalbuminemia), encephalopathy, hypersplenism, coagulopathy, or variceal bleeding may bring the patient to initial medical attention.


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InternalMed_Harrison. The course of autoimmune hepatitis may be variable. In patients with mild disease or limited histologic lesions (e.g., piecemeal necrosis without bridging), progression to cirrhosis is limited, but, even in this subset, clinical monitoring is important to identify progression; up to half left untreated can progress to cirrhosis over the course of 15 years. In North America, cirrhosis at presentation is more common in African Americans than in whites. In those with severe symptomatic autoimmune hepatitis (aminotransferase levels >10 times normal, marked hyperglobulinemia, “aggressive” histologic lesions—bridging necrosis or multilobular collapse, cirrhosis), the 6-month mortality without therapy may be as high as 40%. Such severe disease accounts for only 20% of cases; the natural history of milder disease is variable, often accentuated by spontaneous remissions and exacerbations. Especially poor prognostic signs include the presence histologically of multilobular collapse at the time


InternalMed_Harrison

InternalMed_Harrison. of milder disease is variable, often accentuated by spontaneous remissions and exacerbations. Especially poor prognostic signs include the presence histologically of multilobular collapse at the time of initial presentation and failure of serum bilirubin to improve after 2 weeks of therapy. Death may result from hepatic failure, hepatic coma, other complications of cirrhosis (e.g., variceal hemorrhage), and intercurrent infection. In patients with established cirrhosis, HCC may be a late complication (Chap. 111) but occurs less frequently than in cirrhosis associated with viral hepatitis.


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InternalMed_Harrison. Laboratory features of autoimmune hepatitis are similar to those seen in chronic viral hepatitis. Liver biochemical tests are invariably abnormal but may not correlate with the clinical severity or histopathologic features in individual cases. Many patients with autoimmune hepatitis have normal serum bilirubin, alkaline phosphatase, and globulin levels with only minimal aminotransferase elevations. Serum AST and ALT levels are increased and fluctuate in the range of 100−1000 units. In severe cases, the serum bilirubin level is moderately elevated (51−171 μmol/L [3−10 mg/dL]). Hypoalbuminemia occurs in patients with very active or advanced disease. Serum alkaline phosphatase levels may be moderately elevated or near normal. In a small proportion of patients, marked elevations of alkaline phosphatase activity occur; in such patients, clinical and laboratory features overlap with those of primary biliary cirrhosis (Chap. 365). The prothrombin time is often prolonged, particularly late in


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InternalMed_Harrison. activity occur; in such patients, clinical and laboratory features overlap with those of primary biliary cirrhosis (Chap. 365). The prothrombin time is often prolonged, particularly late in the disease or during active phases.


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InternalMed_Harrison. Hypergammaglobulinemia (>2.5 g/dL) is common in autoimmune hepatitis, as is the presence of rheumatoid factor. As noted above, circulating autoantibodies are also prevalent, most characteristically ANAs in a homogeneous staining pattern. Smooth-muscle antibodies are less specific, seen just as frequently in chronic viral hepatitis. Because of the high levels of globulins achieved in the circulation of some patients with autoimmune hepatitis, occasionally the globulins may bind nonspecifically in solid-phase binding immunoassays for viral antibodies. This has been recognized most commonly in tests for antibodies to hepatitis C virus, as noted above. In fact, studies of auto-antibodies in autoimmune hepatitis have led to the recognition of new categories of autoimmune hepatitis. Type I autoimmune hepatitis is the classic syndrome prevalent in North America and northern Europe occurring in young women, associated with marked hyperglobulinemia, lupoid features, circulating ANAs, and


InternalMed_Harrison

InternalMed_Harrison. autoimmune hepatitis is the classic syndrome prevalent in North America and northern Europe occurring in young women, associated with marked hyperglobulinemia, lupoid features, circulating ANAs, and HLA-DR3 or HLA-DR4 (especially B8-DRB1*03). Also associated with type I autoimmune hepatitis are autoantibodies against actin and atypical perinuclear antineutrophilic cytoplasmic antibodies (pANCA).


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InternalMed_Harrison. Type II autoimmune hepatitis, often seen in children, more common in Mediterranean populations, and linked to HLA-DRB1 and HLA-DQB1 haplotypes, is associated not with ANA but with anti-LKM. Actually, anti-LKM represent a heterogeneous group of antibodies. In type II autoimmune hepatitis, the antibody is anti-LKM1, directed against cytochrome P450 2D6. This is the same anti-LKM seen in some patients with chronic hepatitis C. Anti-LKM2 is seen in drug-induced hepatitis, and anti-LKM3 (directed against uridine diphosphate glucuronyltransferases) is seen in patients with chronic hepatitis D. Another autoantibody observed in type II autoimmune hepatitis is directed against liver cytosol formiminotransferase cyclodeaminase (anti-liver cytosol 1). More controversial is whether or not a third category of autoimmune hepatitis exists, type III autoimmune hepatitis. These patients lack ANA and anti-LKM1 but have circulating antibodies to soluble liver antigen. Most of these patients are women


InternalMed_Harrison

InternalMed_Harrison. of autoimmune hepatitis exists, type III autoimmune hepatitis. These patients lack ANA and anti-LKM1 but have circulating antibodies to soluble liver antigen. Most of these patients are women and have clinical features similar to, perhaps more severe than, those of patients with type I autoimmune hepatitis. Type III autoimmune hepatitis does not appear to represent a distinct category but, instead, is part of the spectrum of type I autoimmune hepatitis; this subcategory has not been adopted by a consensus of international experts.


InternalMed_Harrison

InternalMed_Harrison. Liver biopsy abnormalities are similar to those described for chronic viral hepatitis. Expanding portal tracts and extending beyond the plate of periportal hepatocytes into the parenchyma (designated interface hepatitis or piecemeal necrosis) is a mononuclear cell infiltrate that, in autoimmune hepatitis, may include the presence of plasma cells. Necroinflammatory activity characterizes the lobular parenchyma, and evidence of hepatocellular regeneration is reflected by “rosette” formation, the occurrence of thickened liver cell plates, and regenerative “pseudolobules.” Septal fibrosis, bridging fibrosis, and cirrhosis are frequent. In patients with early autoimmune hepatitis presenting as an acute-hepatitis-like illness, lobular and centrilobular (as opposed to the more common periportal) necrosis has been reported. Bile duct injury and granulomas are uncommon; however, a subgroup of patients with autoimmune hepatitis has histologic, biochemical, and serologic features overlapping


InternalMed_Harrison

InternalMed_Harrison. necrosis has been reported. Bile duct injury and granulomas are uncommon; however, a subgroup of patients with autoimmune hepatitis has histologic, biochemical, and serologic features overlapping those of primary biliary cirrhosis (Chap. 365).


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InternalMed_Harrison. An international group has suggested a set of criteria for establishing a diagnosis of autoimmune hepatitis. Exclusion of liver disease caused by genetic disorders, viral hepatitis, drug hepatotoxicity, and alcohol are linked with such inclusive diagnostic criteria as hyperglobulinemia, autoantibodies, and characteristic histologic features. This international group has also suggested a comprehensive diagnostic scoring system that, rarely required for typical cases, may be helpful when typical features are not present. Factors that weigh in favor of the diagnosis include female gender; predominant aminotransferase elevation; presence and level of globulin elevation; presence of nuclear, smooth muscle, LKM1, and other autoantibodies; concurrent other autoimmune diseases; characteristic histologic features (interface hepatitis, plasma cells, rosettes); HLA-DR3 or -DR4 markers; and response to treatment (see below). A more simplified, more specific scoring system relies on four


InternalMed_Harrison

InternalMed_Harrison. histologic features (interface hepatitis, plasma cells, rosettes); HLA-DR3 or -DR4 markers; and response to treatment (see below). A more simplified, more specific scoring system relies on four variables: autoantibodies, serum IgG level, typical or compatible histologic features, and absence of viral hepatitis markers. Weighing against the diagnosis are predominant alkaline phosphatase elevation, mitochondrial antibodies, markers of viral hepatitis, history of hepatotoxic drugs or excessive alcohol, histologic evidence of bile duct injury, or such atypical histologic features as fatty infiltration, iron overload, and viral inclusions.


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InternalMed_Harrison. Early during the course of chronic hepatitis, autoimmune hepatitis may resemble typical acute viral hepatitis (Chap. 360). Without histologic assessment, severe chronic hepatitis cannot be readily distinguished based on clinical or biochemical criteria from mild chronic hepatitis. In adolescence, Wilson’s disease (Chaps. 365 and 429) may present with features of chronic hepatitis long before neurologic manifestations become apparent and before the formation of Kayser-Fleischer rings (copper deposition in Descemet’s membrane in the periphery of the cornea). In this age group, serum ceruloplasmin and serum and urinary copper determinations plus measurement of liver copper levels establish the correct diagnosis. Postnecrotic or cryptogenic cirrhosis and primary biliary cirrhosis (Chap. 365) share clinical features with autoimmune hepatitis, and both alcoholic hepatitis (Chap. 363) and nonalcoholic steatohepatitis (Chap. 367e) may present with many features common to autoimmune hepatitis;


InternalMed_Harrison

InternalMed_Harrison. clinical features with autoimmune hepatitis, and both alcoholic hepatitis (Chap. 363) and nonalcoholic steatohepatitis (Chap. 367e) may present with many features common to autoimmune hepatitis; historic, biochemical, serologic, and histologic assessments are usually sufficient to allow these entities to be distinguished from autoimmune hepatitis. Of course, the distinction between autoimmune and chronic viral hepatitis is not always straightforward, especially when viral antibodies occur in patients with autoimmune disease or when autoantibodies occur in patients with viral disease. Furthermore, the presence of extrahepatic features such as arthritis, cutaneous vasculitis, or pleuritis—not to mention the presence of circulating autoantibodies—may cause confusion with rheumatologic disorders such as rheumatoid arthritis and systemic lupus erythematosus. The existence of clinical and biochemical features of progressive necroinflammatory liver disease distinguishes chronic hepatitis


InternalMed_Harrison

InternalMed_Harrison. such as rheumatoid arthritis and systemic lupus erythematosus. The existence of clinical and biochemical features of progressive necroinflammatory liver disease distinguishes chronic hepatitis from these other disorders, which are not associated with severe liver disease. Rarely, hepatic venous outflow obstruction (Budd-Chiari syndrome) may present with features suggestive of autoimmune hepatitis, but painful hepatomegaly, ascites, and vascular imaging provide distinguishing diagnostic clues. Other diagnostic considerations would include celiac disease and ischemic liver disease, which would be readily distinguishable by clinical and laboratory features from autoimmune hepatitis.


InternalMed_Harrison

InternalMed_Harrison. Finally, occasionally, features of autoimmune hepatitis overlap with features of autoimmune biliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis (Chaps. 365 and 369), or, even more rarely, mitochondrial antibody-negative autoimmune cholangitis. Such overlap syndromes are difficult to categorize, and often response to therapy may be the distinguishing factor that establishes the diagnosis.


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InternalMed_Harrison. The mainstay of management in autoimmune hepatitis is glucocorticoid therapy. Several controlled clinical trials have documented that such therapy leads to symptomatic, clinical, biochemical, and histologic improvement as well as increased survival. A therapeutic response can be expected in up to 80% of patients. Unfortunately, therapy has not been shown in clinical trials to prevent ultimate progression to cirrhosis; however, instances of reversal of fibrosis and cirrhosis have been reported in patients responding to treatment, and rapid treatment responses within 1 year do translate into a reduction in progression to cirrhosis. Although some advocate the use of prednisolone (the hepatic metabolite of prednisone), prednisone is just as effective and is favored by most authorities. Therapy may be initiated at 20 mg/d, but a popular regimen in the United States relies on an initiation dose of 60 mg/d. This high dose is tapered successively over the course of a month down to a


InternalMed_Harrison

InternalMed_Harrison. Therapy may be initiated at 20 mg/d, but a popular regimen in the United States relies on an initiation dose of 60 mg/d. This high dose is tapered successively over the course of a month down to a maintenance level of 20 mg/d. An alternative, but equally effective, approach is to begin with half the prednisone dose (30 mg/d) along with azathioprine (50 mg/d). With azathioprine maintained at 50 mg/d, the prednisone dose is tapered over the course of a month down to a maintenance level of 10 mg/d. The advantage of the combination approach is a reduction, over the span of an 18-month course of therapy, in serious, life-threatening complications of steroid therapy (e.g., cushingoid features, hypertension, diabetes, osteoporosis) from 66% down to under 20%. Genetic analysis for thiopurine S-methyltransferase allelic variants does not correlate with azathioprine-associated cytopenias or efficacy and is not assessed routinely in patients with autoimmune hepatitis. In combination regimens,


InternalMed_Harrison

InternalMed_Harrison. allelic variants does not correlate with azathioprine-associated cytopenias or efficacy and is not assessed routinely in patients with autoimmune hepatitis. In combination regimens, 6-mercaptopurine may be substituted for its prodrug azathioprine, but this is rarely required. Azathioprine alone, however, is not effective in achieving remission, nor is alternate-day glucocorticoid therapy. Limited experience with budesonide in noncirrhotic patients suggests that this steroid side effect−sparing drug may be effective. Although therapy has been shown to be effective for severe autoimmune hepatitis (AST ≥10 × the upper limit of normal or ≥5 × the upper limit of normal in conjunction with serum globulin greater than or equal to twice normal; bridging necrosis or multilobular necrosis on liver biopsy; presence of symptoms), therapy is not indicated for mild forms of chronic hepatitis, and the efficacy of therapy in mild or asymptomatic autoimmune hepatitis has not been established.


InternalMed_Harrison

InternalMed_Harrison. Improvement of fatigue, anorexia, malaise, and jaundice tends to occur within days to several weeks; biochemical improvement occurs over the course of several weeks to months, with a fall in serum bilirubin and globulin levels and an increase in serum albumin. Serum aminotransferase levels usually drop promptly, but improvements in AST and ALT alone do not appear to be reliable markers of recovery in individual patients; histologic improvement, characterized by a decrease in mononuclear infiltration and in hepatocellular necrosis, may be delayed for 6−24 months. Still, if interpreted cautiously, aminotransferase levels are valuable indicators of relative disease activity, and many authorities do not advocate for serial liver biopsies to assess therapeutic success or to guide decisions to alter or stop therapy. Rapidity of response is more common in older patients (≥69 years) and those with HLA DBR1*04; although rapid responders may progress less slowly to cirrhosis and liver


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InternalMed_Harrison. to alter or stop therapy. Rapidity of response is more common in older patients (≥69 years) and those with HLA DBR1*04; although rapid responders may progress less slowly to cirrhosis and liver transplantation, they are no less likely than slower responders to relapse after therapy. Therapy should continue for at least 12−18 months. After tapering and cessation of therapy, the likelihood of relapse is at least 50%, even if posttreatment histology has improved to show mild chronic hepatitis, and the majority of patients require therapy at maintenance doses indefinitely. Continuing azathioprine alone (2 mg/kg body weight daily) after cessation of prednisone therapy has been shown to reduce the frequency of relapse. Long-term maintenance with low-dose prednisone (≤10 mg daily) has also been shown to keep autoimmune hepatitis in check, but maintenance azathioprine is more effective in maintaining remission.


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InternalMed_Harrison. 2052 In medically refractory cases, an attempt should be made to intensify treatment with high-dose glucocorticoid monotherapy (60 mg daily) or combination glucocorticoid (30 mg daily) plus high-dose azathioprine (150 mg daily) therapy. After a month, doses of prednisone can be reduced by 10 mg a month, and doses of azathioprine can be reduced by 50 mg a month toward ultimate, conventional maintenance doses. Patients refractory to this regimen may be treated with cyclosporine, tacrolimus, or mycophenolate mofetil; however, to date, only limited anecdotal reports support these approaches. If medical therapy fails, or when chronic hepatitis progresses to cirrhosis and is associated with life-threatening complications of liver decompensation, liver transplantation is the only recourse (Chap. 368); failure of the bilirubin to improve after 2 weeks of therapy should prompt early consideration of the patient for liver transplantation. Recurrence of autoimmune hepatitis in the new liver


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InternalMed_Harrison. 368); failure of the bilirubin to improve after 2 weeks of therapy should prompt early consideration of the patient for liver transplantation. Recurrence of autoimmune hepatitis in the new liver occurs rarely in most experiences but in as many as 35−40% of cases in others. Like all patients with chronic liver disease, patients with autoimmune hepatitis should be vaccinated against hepatitis A and B, ideally before immunosuppressive therapy is begun, if practical.


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InternalMed_Harrison. Disorders of the Gastrointestinal System Kurt J. Isselbacher, MD, contributed to this chapter in previous editions of Harrison’s. Mark E. Mailliard, Michael F. Sorrell


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InternalMed_Harrison. Chronic and excessive alcohol ingestion is one of the major causes of liver disease. The pathology of alcoholic liver disease consists of three major lesions, with the progressive injury rarely existing in a pure form: (1) fatty liver, (2) alcoholic hepatitis, and (3) cirrhosis. Fatty liver is present in >90% of daily as well as binge drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; the mortality of patients with alcoholic hepatitis concurrent with cirrhosis is nearly 60% at 4 years. Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of alcoholics will develop alcoholic hepatitis. The explanation for this apparent paradox is unclear but involves the complex interaction of facilitating factors, such as drinking patterns, diet, obesity, and gender. There are no diagnostic tools that can predict individual susceptibility


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InternalMed_Harrison. is unclear but involves the complex interaction of facilitating factors, such as drinking patterns, diet, obesity, and gender. There are no diagnostic tools that can predict individual susceptibility to alcoholic liver disease.


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InternalMed_Harrison. Alcohol is the world’s third largest risk factor for disease bur den. The harmful use of alcohol results in 2.5 million deaths each year. Most of the mortality attributed to alcohol is secondary to cirrhosis. Mortality from cirrhosis is declining in most Western countries, concurrent with a reduction in alcohol consumption, with the exceptions of the United Kingdom, Russia, Romania, and Hungary. These increases in cirrhosis and its complications are closely correlated with increased volume of alcohol consumed per capita population and are regardless of gender.


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InternalMed_Harrison. Quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver disease (Table 363-1). The roles of beverage type(s), i.e. wine, beer, or spirits, and pattern of drinking (daily versus binge drinking) are less clear. Progress beyond the fatty liver stage seems to require additional risk factors that remain incompletely defined. Although there are genetic predispositions for alcoholism (Chap. 467), gender is a strong determinant for alcoholic liver disease. Women are more susceptible to alcoholic liver injury when compared to men. They develop advanced liver disease with substantially less alcohol intake. In general, the time it takes to develop liver disease is directly related to the amount of alcohol consumed. It is useful in estimating alcohol consumption to understand that one beer, four ounces of wine, or one ounce of 80% spirits all contain ∼12 g of alcohol. The threshold for developing alcoholic liver disease is higher


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InternalMed_Harrison. alcohol consumption to understand that one beer, four ounces of wine, or one ounce of 80% spirits all contain ∼12 g of alcohol. The threshold for developing alcoholic liver disease is higher in men, while women are at increased risk for developing similar degrees of liver injury by consuming significantly less. Gender-dependent differences result from poorly understood effects of estrogen, proportion of body fat, and the gastric metabolism of alcohol. Obesity, a high-fat diet, and the protective effect of coffee have been postulated to play a part in the development of the pathogenic process.


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InternalMed_Harrison. Chronic infection with hepatitis C virus (HCV) (Chap. 362) is an important comorbidity in the progression of alcoholic liver disease to cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of 20–50 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected individuals. Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. Increased liver iron stores and, rarely, porphyria cutanea tarda can occur as a consequence of the overlapping injurious processes secondary to alcohol abuse and HCV infection. In addition, alcohol intake of >50 g/d by HCV-infected patients decreases the efficacy of interferon-based antiviral therapy.


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InternalMed_Harrison. The pathogenesis of alcoholic liver injury is unclear. The present conceptual foundation is that alcohol acts as a direct hepatotoxin and that malnutrition does not have a major role. Ingestion of alcohol initiates an inflammatory cascade by its metabolism to acetaldehyde, resulting in a variety of metabolic responses. Steatosis from lipogenesis, fatty acid synthesis, and depression of fatty acid oxidation appears secondary to effects on sterol regulatory transcription factor and peroxisome proliferator-activated receptor α (PPAR-α). Intestinal-derived endotoxin initiates a pathogenic process through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that facilitates hepatocyte apoptosis and necrosis. The cell injury and endotoxin release initiated by ethanol and its metabolites also activate innate and adaptive immunity pathways releasing proinflammatory cytokines (e.g., TNF-α), chemokines, and proliferation of T and B cells. The production of toxic protein-aldehyde adducts,


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InternalMed_Harrison. activate innate and adaptive immunity pathways releasing proinflammatory cytokines (e.g., TNF-α), chemokines, and proliferation of T and B cells. The production of toxic protein-aldehyde adducts, generation of reducing equivalents, and oxidative stress also contribute to the liver injury. Hepatocyte injury and impaired regeneration following chronic alcohol ingestion are ultimately associated with stellate cell activation and collagen production, which are key events in fibrogenesis. The resulting fibrosis from continuing alcohol use determines the architectural derangement of the liver and associated pathophysiology.


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InternalMed_Harrison. The liver has a limited repertoire in response to injury. Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excessive alcohol ingestion. The accumulation of fat within the perivenular hepatocytes coincides with the location of alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism. Continuing alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of hepatic architecture and fat content. Alcoholic fatty liver has traditionally been regarded as entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease (Chap. 367e), the appearance of steatohepatitis and certain pathologic features such as giant mitochondria, perivenular fibrosis, and macrovesicular fat may be associated with progressive liver injury.


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InternalMed_Harrison. The transition between fatty liver and the development of alcoholic hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the perivenular and perisinusoidal space of Disse. Mallory-Denk bodies are often present in florid cases but are neither specific nor necessary to establish the diagnosis. Alcoholic hepatitis is thought to be a precursor to the development of cirrhosis. However, like fatty liver, it is potentially reversible with cessation of drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis, and its regression is uncertain, even with abstention.


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InternalMed_Harrison. The clinical manifestations of alcoholic fatty liver are subtle and characteristically detected as a consequence of the patient’s visit for a seemingly unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally, patients with fatty liver will present with right upper quadrant discomfort, nausea, and, rarely, jaundice. Differentiation of alcoholic fatty liver from nonalcoholic fatty liver is difficult unless an accurate drinking history is ascertained. In every instance where liver disease is present, a thoughtful and sensitive drinking history should be obtained. Standard, validated questions accurately detect alcohol-related problems (Chap. 467). Alcoholic hepatitis is associated with a wide gamut of clinical features. Fever, spider nevi, jaundice, and abdominal pain simulating an acute abdomen represent the extreme end of the spectrum, while many patients will be entirely asymptomatic. Portal hypertension, ascites, or variceal bleeding can


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InternalMed_Harrison. and abdominal pain simulating an acute abdomen represent the extreme end of the spectrum, while many patients will be entirely asymptomatic. Portal hypertension, ascites, or variceal bleeding can occur in the absence of cirrhosis. Recognition of the clinical features of alcoholic hepatitis is central to the initiation of an effective and appropriate diagnostic and therapeutic strategy. It is important to recognize that patients with alcoholic cirrhosis often exhibit clinical features identical to other causes of cirrhosis.


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InternalMed_Harrison. Patients with alcoholic liver disease are often identified through routine screening tests. The typical laboratory abnormalities seen in fatty liver are nonspecific and include modest elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (GGTP), often accompanied by hypertriglyceridemia and hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of fatty liver, AST and ALT are usually elevated twoto sevenfold. They are rarely >400 IU, and the AST/ALT ratio is >1 (Table 363-2). Hyperbilirubinemia is accompanied by modest increases in the alkaline phosphatase level. Derangement in hepatocyte synthetic function indicates more serious disease. Hypoalbuminemia and coagulopathy are common in advanced liver injury. Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal venous


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InternalMed_Harrison. Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal venous collaterals indicates serious liver injury with less potential for complete reversal.


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InternalMed_Harrison. AST Increased twoto sevenfold, <400 IU/L, greater than ALT ALT Increased twoto sevenfold, <400 IU/L GGTP Not specific to alcohol, easily inducible, elevated in all forms of fatty liver Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGTP, γ-glutamyl transpeptidase.


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InternalMed_Harrison. Critically ill patients with alcoholic hepatitis have short-term (30-day) mortality rates >50%. Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin time increased >5 s), anemia, serum albumin concentrations <25 g/L (2.5 mg/dL), serum bilirubin levels >137 μmol/L (8 mg/dL), renal failure, and ascites. A discriminant function calculated as 4.6 X (the prolongation of the prothrombin time above control [seconds]) + serum bilirubin (mg/dL) can identify patients with a poor prognosis (discriminant function >32). A Model for End-Stage Liver Disease (MELD) score (Chap. 368) ≥21 also is associated with significant mortality in alcoholic hepatitis. The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. The pathologic stage of the injury can be helpful in predicting prognosis. Liver biopsy should be performed whenever possible to establish the diagnosis and to guide the therapeutic decisions.


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InternalMed_Harrison. Complete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologic injury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion. Referral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routine in the management of patients with alcoholic liver disease. Attention should be directed to the nutritional and psychosocial states during the evaluation and treatment periods. Because of data suggesting that the pathogenic mechanisms in alcoholic hepatitis involve cytokine release and the perpetuation of injury by immunologic processes, glucocorticoids have been extensively evaluated in the treatment of alcoholic hepatitis. Patients with severe alcoholic hepatitis, defined as a discriminant function >32 or MELD >20, should be given prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks, followed by a


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InternalMed_Harrison. hepatitis. Patients with severe alcoholic hepatitis, defined as a discriminant function >32 or MELD >20, should be given prednisone, 40 mg/d, or prednisolone, 32 mg/d, for 4 weeks, followed by a steroid taper (Fig. 363-1). Exclusion criteria include active gastrointestinal bleeding, renal failure, or pancreatitis. Women with encephalopathy from severe alcoholic hepatitis may be particularly good candidates for glucocorticoids. A Lille score >0.45, at http://www.lillemodel.com, uses pretreatment variables plus the change in total bilirubin at day 7 of glucocorticoids to identify patients unresponsive to therapy.


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InternalMed_Harrison. The role of TNF-α expression and receptor activity in alcoholic liver injury has led to an examination of TNF inhibition as an alternative to glucocorticoids for severe alcoholic hepatitis. The nonspecific TNF inhibitor, pentoxifylline, demonstrated improved survival in the therapy of severe alcoholic hepatitis, primarily due to a decrease in hepatorenal syndrome (Fig. 363-2). Monoclonal antibodies that neutralize serum TNF-α should not be used in alcoholic hepatitis because of studies reporting increased deaths secondary to infection and renal failure.


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InternalMed_Harrison. Liver transplantation is an accepted indication for treatment in selected and motivated patients with end-stage cirrhosis. Outcomes are equal or superior to other indications for transplantation. In general, transplant candidacy should be reevaluated after a defined 0 7 14 21 84.6 3.4% p = .001 65.1 4.8% 28 nonalcoholic fatty liver Diseases and nonalcoholic Steatohepatitis Manal F. Abdelmalek, Anna Mae Diehl INCIDENCE, PREVALENCE, AND NATURAL HISTORY Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in many parts of the world, including the United States. 364


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InternalMed_Harrison. FIGURE 363-1 Effect of glucocorticoid therapy of severe alcoholic hepatitis on short-term survival: the result of a meta-analysis of individual data from three studies. Prednisolone, solid line; placebo, dotted line. (Adapted from P Mathurin et al: J Hepatol 36:480, 2002, with permission from Elsevier Science.) period of sobriety. Patients presenting with alcoholic hepatitis have been largely excluded from transplant candidacy because of the perceived risk of increased surgical mortality and high rates of recidivism following transplantation. Recently, a European multidisciplinary group has reported excellent long-term transplant outcomes in highly selected patients with florid alcoholic hepatitis. General application of transplantation in such patients must await confirmatory outcomes by others. Cumulative survival, %


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InternalMed_Harrison. Cumulative survival, % Alcoholic Hepatitis Alcohol abstinence Nutritional support Treatment options Preferred Alternative Discriminant function ˜ 32 or MELD ˜ 21 (with absence of co-morbidity) Prednisolone 32 mg p.o. daily for 4 weeks, then taper for 4 weeks Pentoxifylline 400 mg p.o. TID for 4 weeks FIGURE 363-2 Treatment algorithm for alcoholic hepatitis. As identified by a calculated discriminant function >32 (see text), patients with severe alcoholic hepatitis, without the presence of gastrointestinal bleeding or infection, would be candidates for either glucocorticoids or pentoxifylline administration.


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InternalMed_Harrison. Population-based abdominal imaging studies have demonstrated fatty liver in at least 25% of American adults. Because the vast majority of these subjects deny hazardous levels of alcohol consumption (defined as greater than one drink per day in women or two drinks per day in men), they are considered to have NAFLD. NAFLD is strongly associated with overweight/obesity and insulin resistance. However, it can also occur in lean individuals and is particularly common in those with a paucity of adipose depots (i.e., lipodystrophy). Ethnic/racial factors also appear to influence liver fat accumulation; the documented prevalence of NAFLD is lowest in African Americans (~25%), highest in Americans of Hispanic ancestry (~50%), and intermediate in American whites (~33%).


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InternalMed_Harrison. NAFLD encompasses a spectrum of liver pathology with different clinical prognoses. The simple accumulation of triglyceride within hepatocytes (hepatic steatosis) is on the most clinically benign extreme of the spectrum. On the opposite, most clinically ominous extreme, are cirrhosis (Chap. 365) and primary liver cancer (Chap. 111). The risk of developing cirrhosis is extremely low in individuals with chronic hepatic steatosis, but increases as steatosis becomes complicated by histologically conspicuous hepatocyte death and inflammation (i.e., nonalcoholic steatohepatitis [NASH]). NASH itself is also a heterogeneous condition; sometimes it improves to steatosis or normal histology, sometimes it remains relatively stable for years, but sometimes it results in progressive accumulation of fibrous scar that eventuates in cirrhosis. Once NAFLD-related cirrhosis develops, the annual incidence of primary liver cancer is 1%.


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InternalMed_Harrison. Abdominal imaging is not able to determine which individuals with NAFLD have associated liver cell death and inflammation (i.e., NASH), and specific blood tests to diagnose NASH are not yet available. However, population-based studies that have used elevated serum ALT as a marker of liver injury indicate that about 6–8% of American adults have serum ALT elevations that cannot be explained by excessive alcohol consumption, other known causes of fatty liver disease (Table 364-1), viral hepatitis, or drug-induced or congenital liver diseases. Because the prevalence of such “cryptogenic” ALT elevations increases with body mass index, it is presumed that they are due to NASH. Hence, at any given point in time, NASH is present in about 25% of individuals who have NAFLD (i.e., about 6% of the general


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InternalMed_Harrison. U.S. adult population has NASH). Smaller cross-sectional studies in which liver biopsies have been performed on NASH patients at tertiary referral centers consistently demonstrate advanced fibrosis or cirrhosis in about 25% of those cohorts. By extrapolation, therefore, cirrhosis develops in about 6% of individuals with NAFLD (i.e., in about 1.5–2% of the general U.S. population). The risk for advanced liver fibrosis is highest in individuals with NASH who are older than 45–50 years of age and overweight/obese or afflicted with type 2 diabetes.


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InternalMed_Harrison. To put these data in perspective, it is helpful to recall that the prevalence of hepatitis C–related cirrhosis in the United States is about 0.5%. Thus, NAFLD-related cirrhosis is about three to four times more common than cirrhosis caused by chronic hepatitis C infection. Consistent with these data, experts have predicted that NAFLD will surpass hepatitis C as the leading indication for liver transplantation in the United States within the next decade. Similar to cirrhosis caused by other liver diseases, cirrhosis caused by NAFLD increases the risk for primary liver cancer. Both hepatocellular carcinoma and intrahepatic cholangiocarcinoma (ICC) have also been reported to occur in NAFLD patients without cirrhosis, suggesting that NAFLD per se may be a premalignant condition. NAFLD, NASH, and NAFLD-related cirrhosis are not limited to adults. All have been well documented in children. As in adults, obesity and insulin resistance are the main risk


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InternalMed_Harrison. AlTERnATiVE CAuSES of HEPATiC STEAToSiS errors of metabolism exposure to petrochemical fatty liver of pregnancy syndrome (hemolytic anemia, elevated liver enzymes, low platelet count) factors for pediatric NAFLD. Thus, the rising incidence and prevalence of childhood obesity suggests that NAFLD is likely to become an even greater contributor to society’s burden of liver disease in the future.


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InternalMed_Harrison. The mechanisms underlying the pathogenesis and progression of NAFLD are not entirely clear. The best-understood mechanisms pertain to hepatic steatosis. This is proven to result when hepatocyte mechanisms for triglyceride synthesis (e.g., lipid uptake and de novo lipogenesis) overwhelm mechanisms for triglyceride disposal (e.g., degradative metabolism and lipoprotein export), leading to accumulation of fat (i.e., triglyceride) within hepatocytes. Obesity stimulates hepatocyte triglyceride accumulation by altering the intestinal microbiota to enhance both energy harvest from dietary sources and intestinal permeability. Reduced intestinal barrier function increases hepatic exposure to gut-derived products, which stimulate liver cells to generate inflammatory mediators that inhibit insulin actions. Obese adipose depots also produce excessive soluble factors (adipokines) that inhibit tissue insulin sensitivity. Insulin resistance promotes hyperglycemia. This drives the pancreas to produce


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InternalMed_Harrison. Obese adipose depots also produce excessive soluble factors (adipokines) that inhibit tissue insulin sensitivity. Insulin resistance promotes hyperglycemia. This drives the pancreas to produce more insulin to maintain glucose homeostasis. However, hyperinsulinemia also promotes lipid uptake, fat synthesis, and fat storage. The net result is hepatic triglyceride accumulation (i.e., steatosis).


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InternalMed_Harrison. Triglyceride per se is not hepatotoxic. However, its precursors (e.g., fatty acids and diacylglycerols) and metabolic by-products (e.g., reactive oxygen species) may damage hepatocytes, leading to hepatocyte lipotoxicity. Lipotoxicity also triggers the generation of other factors (e.g., inflammatory cytokines, hormonal mediators) that deregulate systems that normally maintain hepatocyte viability. The net result is increased hepatocyte death. Dying hepatocytes, in turn, release various factors that trigger wound healing responses that aim to replace (regenerate) lost hepatocytes. Such repair involves transient 2055 expansion of other cell types, such as myofibroblasts and progenitor cells, that make and degrade matrix, remodel the vasculature, and generate replacement hepatocytes, as well as the recruitment of immune cells that release factors that modulate liver injury and repair. NASH is the morphologic manifestation of lipotoxicity and resultant wound healing responses. Because the