Hepatology, in full.

Diagnose MASLD by hepatic steatosis on imaging (or biopsy) plus at least one cardiometabolic criterion and exclusion of competing etiologies (significant alcohol use, other liver disease), then risk-stratify fibrosis using a sequential non-invasive approach: FIB-4 first, followed by a second-line imaging-based test (VCTE, MRE, or ELF) for indeterminate/high-risk FIB-4, with liver biopsy reserved for discordant or unclear cases. Lifestyle modification (≥7-10% weight loss, Mediterranean diet, exercise) remains the foundation for all patients. For adults with MASH and F2-F3 fibrosis identified by non-invasive tests (VCTE 8-15 kPa, MRE 3.1-4.4 kPa, or ELF 9.2-10.5) rather than biopsy, AASLD now gives dedicated, updated practice guidance on both FDA-approved pharmacotherapies: resmetirom (Oct 2024 update) and semaglutide 2.4mg/week subcutaneous (Nov 2025 update, following August 2025 accelerated FDA approval based on ESSENCE trial data: 62.9% vs 34.3% MASH resolution without fibrosis worsening; 36.8% vs 22.4% ≥1-stage fibrosis improvement). Pioglitazone or vitamin E remain options per the 2023 base guidance. Manage cardiometabolic risk with statins for ASCVD reduction plus glycemic and blood-pressure control; for semaglutide specifically, routine hepatic panels are recommended only as clinically indicated (no discontinuations for LFT elevation in ESSENCE), with monitoring for GI adverse effects and rare risks (AKI, gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, lean mass loss). HCC surveillance with ultrasound and AFP every 6 months remains indicated only if cirrhosis is present.

Treatment of AUD with sustained abstinence is the most effective strategy to prevent progression and improve long-term outcomes at any stage of ALD; ACG recommends brief screening with a tool such as AUDIT-C (strong, high), brief motivational interventions (strong, low), and integrated multidisciplinary care combining behavioral therapy and/or pharmacotherapy (strong, low). AUD pharmacotherapy recommendations are scoped specifically to COMPENSATED ALD and are not co-equal: baclofen is recommended as an option (strong recommendation, moderate evidence); acamprosate or naltrexone are only suggested as options (conditional, very low); gabapentin or topiramate are suggested as options (conditional, very low); disulfiram is suggested AGAINST along any spectrum of ALD (conditional, very low). For severe alcohol withdrawal, benzodiazepines are the treatment of choice but with explicitly cautious use and careful monitoring given their potential to precipitate or exacerbate hepatic encephalopathy (strong, moderate); AWS is managed per CIWA-Ar protocol, differentiating it from HE while acknowledging the two can coexist. For alcohol-associated hepatitis (AH), severity is stratified by MELD: MELD >20 defines severe AH, which carries high short-term mortality and should preferably be managed in hospital; MELD ≤20 defines moderate AH. In severe AH (MELD >20) ACG recommends corticosteroid therapy ONLY if there are no contraindications (strong, moderate); active infection (including untreated HBV infection), uncontrolled diabetes mellitus, gastrointestinal bleeding, and severe renal failure are contraindications to corticosteroid use, though corticosteroids can be started after adequate control or reversal of infection, renal failure, and gastrointestinal bleeding. Prednisolone is preferred over prednisone; both are dosed 40 mg/day for a total of 4 weeks, with IV methylprednisolone 32 mg/day as the alternative for patients unable to take oral medication; there is no evidence supporting rapid vs slow tapering after the 4-week course. Corticosteroid response is assessed by Lille score at day 7 OR day 4 (day-4 shown as accurate as day-7); among non-responders (Lille >0.45) corticosteroids should be discontinued. ACG recommends IV N-acetylcysteine as an adjuvant to corticosteroids in severe AH (strong, moderate), while explicitly noting that other society guidelines have not adopted this recommendation. ACG recommends AGAINST pentoxifylline (strong, moderate) and AGAINST universal prophylactic antibiotics in hospitalized severe AH (strong, moderate); data on G-CSF and microbiome-based therapies are insufficient. Nutrition: target 35 kcal/kg/day with 1.2-1.5 g/kg/day protein; patients consuming <21 kcal/kg/day should receive nutritional support, preferably oral/enteral, oral nutritional supplements first, escalating to enteral nutrition if caloric targets remain unmet (strong, moderate). Thiamine, vitamin B12 and zinc deficiencies are common in AH and should be supplemented. For severe AH unresponsive to medical management with high risk of death, early liver transplantation for highly selected patients should be considered according to regional and institutional protocols (conditional recommendation, low level of evidence); LT selection must not be based solely on an arbitrary duration of sobriety, and should rest on detailed psychosocial evaluation by a social worker and addiction specialist, optionally supported by tools such as SIPAT, HRAR, MAPS, HPSS or SALT. For severe AH with 4 or more organ failures, non-responsive to corticosteroids and ineligible for early LT, palliative care engagement is appropriate.

Test only patients with symptoms suggestive of active CDI (≥3 unformed stools in 24 hours); testing patients with formed stool is rarely clinically indicated. Use a testing algorithm including both a highly sensitive and a highly specific modality to distinguish colonization from active infection (conditional recommendation, low quality evidence): begin with a highly sensitive test (GDH or NAAT), and if positive proceed to the more specific toxin EIA. A sensitive-test-positive/toxin-EIA-negative result means not CDI or colonization, a false-negative EIA, or toxin below detection, it requires clinical evaluation, and treatment should not be withheld when clinical suspicion is high, because no test is perfect and the diagnosis is a clinical one. Classify as severe when WBC ≥15,000 cells/mm3 or serum creatinine >1.5 mg/dL; classify as fulminant when severe criteria are met plus hypotension or shock, or ileus, or megacolon. INITIAL NONSEVERE EPISODE, ACG gives two co-equal strong recommendations, not a preference: oral vancomycin 125 mg 4 times daily for 10 days (strong recommendation, low quality) OR oral fidaxomicin 200 mg twice daily for 10 days (strong recommendation, moderate quality); oral metronidazole 500 mg 3 times daily for 10 days may be considered for an initial nonsevere episode in LOW-RISK patients (strong recommendation, moderate quality), ACG explicitly retains metronidazole as an appropriate alternative for lower-risk patients (younger outpatients with minimal comorbidities, cost-sensitive environments). SEVERE CDI, vancomycin 125 mg 4 times daily for 10 days (strong, low quality) or fidaxomicin 200 mg twice daily for 10 days (conditional, very low quality). FULMINANT CDI, adequate volume resuscitation plus oral vancomycin 500 mg every 6 hours for the first 48-72 hours (strong recommendation, very low quality); combination therapy with parenteral metronidazole 500 mg every 8 hours can be considered (conditional, very low); for patients with ileus, adding vancomycin enemas 500 mg every 6 hours may be beneficial (conditional, very low); FMT is suggested for severe and fulminant CDI refractory to antibiotic therapy, particularly when patients are poor surgical candidates (strong recommendation, low quality). Surgical options (total colectomy with end ileostomy vs diverting loop ileostomy with colonic lavage and intraluminal vancomycin) depend on clinical circumstances and surgeon judgment. FIRST RECURRENCE, tapering/pulsed-dose vancomycin after an initial course of fidaxomicin, vancomycin, or metronidazole (strong recommendation, very low quality), or fidaxomicin after an initial course of vancomycin or metronidazole (strong recommendation, moderate quality). SECOND OR FURTHER RECURRENCE, treat with FMT to prevent further recurrences (strong recommendation, moderate quality), delivered by colonoscopy or capsules (strong, moderate), with enema suggested only if other methods are unavailable (conditional, low); repeat FMT is suggested for recurrence within 8 weeks of an initial FMT (conditional, very low). Suppressive oral vancomycin may be used to prevent further recurrences in rCDI patients who are not FMT candidates, who relapsed after FMT, or who require ongoing/frequent antibiotics (conditional, very low). Bezlotoxumab is suggested for prevention of CDI recurrence in patients at HIGH RISK OF RECURRENCE (conditional recommendation, moderate quality), ACG ties it to recurrence risk, not to a specific recurrence number. Antisecretory therapy should not be discontinued in patients with CDI provided there is an appropriate indication for its use (strong, very low). IBD, test for C. difficile in patients with IBD presenting with an acute flare associated with diarrhea (strong, low); vancomycin 125 mg 4 times daily for a MINIMUM OF 14 DAYS in patients with IBD and CDI (strong, very low); FMT should be considered for recurrent CDI in IBD (strong, very low). Vancomycin is recommended for pregnant, peripartum, and breastfeeding patients; vancomycin or fidaxomicin first line if immunocompromised. Do NOT test for cure: routine testing in asymptomatic patients after treatment is not recommended, because persistent shedding occurs in 56% of patients who had resolution of diarrhea as long as 4 weeks after completing treatment.

Diagnose MASLD by hepatic steatosis on imaging (or biopsy) plus at least one cardiometabolic criterion and exclusion of competing etiologies (significant alcohol use, other liver disease), then risk-stratify fibrosis using a sequential non-invasive approach: FIB-4 first, followed by a second-line imaging-based test (VCTE, MRE, or ELF) for indeterminate/high-risk FIB-4, with liver biopsy reserved for discordant or unclear cases. Lifestyle modification (≥7-10% weight loss, Mediterranean diet, exercise) remains the foundation for all patients. For adults with MASH and F2-F3 fibrosis identified by non-invasive tests (VCTE 8-15 kPa, MRE 3.1-4.4 kPa, or ELF 9.2-10.5) rather than biopsy, AASLD now gives dedicated, updated practice guidance on both FDA-approved pharmacotherapies: resmetirom (Oct 2024 update) and semaglutide 2.4mg/week subcutaneous (Nov 2025 update, following August 2025 accelerated FDA approval based on ESSENCE trial data: 62.9% vs 34.3% MASH resolution without fibrosis worsening; 36.8% vs 22.4% ≥1-stage fibrosis improvement). Pioglitazone or vitamin E remain options per the 2023 base guidance. Manage cardiometabolic risk with statins for ASCVD reduction plus glycemic and blood-pressure control; for semaglutide specifically, routine hepatic panels are recommended only as clinically indicated (no discontinuations for LFT elevation in ESSENCE), with monitoring for GI adverse effects and rare risks (AKI, gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, lean mass loss). HCC surveillance with ultrasound and AFP every 6 months remains indicated only if cirrhosis is present.

Perform HCC surveillance in adults with cirrhosis of any etiology who are able to benefit from HCC treatment, accordingly, do not enroll patients with Child-Turcotte-Pugh class C cirrhosis unless they are candidates for (or listed for) liver transplantation, and do not surveil those with life-limiting comorbidity (life expectancy <1-2 years) that transplantation cannot remedy, and in select non-cirrhotic chronic HBV carriers at elevated risk (e.g., active hepatitis/high viral load, family history of HCC, African/African-American ancestry, Asian men >40 and Asian women >50; AASLD references risk scores such as PAGE-B but stops short of mandating a specific numeric cutoff). Surveillance is abdominal ultrasound PLUS serum AFP at ~6-month (semiannual) intervals, a change from prior AASLD guidance, which had left AFP optional (Strong recommendation). Pursue diagnostic evaluation for an AFP ≥20 ng/mL or for a rising AFP, defined as a doubling of AFP or an increase on two consecutive tests even if the absolute value is <20 ng/mL. Any suspicious ultrasound observation ≥1 cm, or an inadequate/limited ultrasound, should be evaluated with multiphasic contrast-enhanced CT or MRI interpreted with CT/MRI LI-RADS. AASLD 2023 stages confirmed HCC using the BCLC framework and links stage to therapy (curative resection, ablation, or transplantation within Milan criteria for very-early/early disease; TACE and other locoregional therapy for intermediate disease; systemic therapy for advanced disease). Its first-line systemic options for advanced HCC with preserved liver function (Child-Pugh A) are atezolizumab+bevacizumab OR durvalumab+tremelimumab (STRIDE) as preferred, with sorafenib, lenvatinib, or durvalumab monotherapy as alternatives when the preferred combinations are contraindicated. After potentially curative therapy, continue surveillance for recurrence given high recurrence risk (AASLD monitors with cross-sectional contrast-enhanced imaging, not ultrasound, in the early post-treatment period).

The 2026 AASLD/IDSA guideline addresses six PICO questions only; it states explicitly that all other 2018 AASLD recommendations for CHB management remain applicable, and that screening/diagnosis were out of scope. Baseline evaluation and the standard treatment indications (cirrhosis with detectable HBV DNA; HBeAg-positive immune-active with ALT >2x ULN and HBV DNA >20,000 IU/mL; HBeAg-negative immune-active with ALT >2x ULN and HBV DNA >2,000 IU/mL; prophylaxis for reactivation risk during immunosuppression) derive from the 2018 document, not this update, which lists 'treatment of HBeAg-positive and -negative immune active CHB with ALT >2x ULN', treatment of children, treatment of cirrhosis, low-level viremia, virologic breakthrough, and special populations (transplant, acute HBV, HCV/HDV/HIV coinfection) as topics 'well covered in previous AASLD 2018 Guidance and for which recommendations have not changed'. Preferred agents remain entecavir, TDF, or TAF. THE SIX 2026 RECOMMENDATIONS: (1) PMTCT, for pregnant persons with HBV DNA >200,000 IU/mL at any time point during pregnancy, regardless of HBeAg status, AASLD RECOMMENDS initiating TDF or TAF at gestational week 28 (STRONG recommendation, MODERATE certainty, the only strong recommendation in the guideline); TDF has a more extensive safety record in pregnancy than TAF. Implementation qualifiers: initiate immediately if care is first sought after week 28; initiate at week 16 if infant HBIG will be unavailable (with subsequent infant vaccination); consider earlier initiation when amniocentesis is anticipated (transmission risk is increased with HBV DNA >2,000,000 IU/mL) or when preterm labor risk is high; continue TDF/TAF if already on it, switch entecavir or other agents to TDF/TAF; if treatment was solely for perinatal prophylaxis it may be discontinued at delivery, with HBV DNA and ALT monitored every 1-3 months for up to 6 months for withdrawal flare and treatment reinitiated if ALT >=5x ULN; use TDF or TAF in breastfeeding persons requiring treatment. (2) HORIZONTAL TRANSMISSION, for HBsAg-positive viremic persons not meeting disease-specific treatment indications who are in high-risk scenarios for transmission to others, AASLD SUGGESTS a shared decision-making approach regarding antiviral treatment (CONDITIONAL, VERY LOW certainty). Qualifiers the guideline stresses: the decision weighs exposure risk and the vaccine/immunity status of contacts, favoring treatment if contacts are unvaccinated, vaccine-nonresponsive, immunocompromised, or of unknown vaccine status; persons requesting treatment for prevention may be prescribed it since risks may not be disclosed; explicitly, people with CHB must NOT be restricted in daily activities, contact sports, school, or professional training and must NOT be required to take antivirals because of transmission risk in those settings; routine contact, shared meals, and hugging are not transmission routes (avoid sharing toothbrushes/razors); most healthcare workers with CHB are NOT high-risk, but those performing SHEA Category III exposure-prone procedures may require antivirals (SHEA target HBV DNA <1000 IU/mL); neither CDC nor SHEA requires disclosure to patients or staff; anti-stigma framing is part of the recommendation. (3) IMMUNE-TOLERANT PHASE, defined as HBeAg-positive, HBV DNA >10^7 IU/mL, and normal ALT; AASLD SUGGESTS antiviral therapy for those over age 40 years, OR with significant liver inflammation (grade >=2) or fibrosis (>=F2) on biopsy or noninvasive tests (CONDITIONAL, VERY LOW certainty). For persons under age 40 who are interested in starting treatment earlier, AASLD suggests shared decision-making weighing risk factors and the benefits and risks of treatment. Accurate phase identification requires persistently normal ALT on >=2 measurements >=6 months apart, using ULN 35 U/L (males) and 25 U/L (females). (4) INDETERMINATE ('grey zone') PHASE, the HBeAg-negative indeterminate phase is defined as HBsAg-positive, HBeAg-negative persons whose ALT and/or HBV DNA fall outside the thresholds for HBeAg-negative immune-active CHB (ALT >2x ULN and HBV DNA >2,000 IU/mL) and outside those for inactive CHB (HBV DNA <2,000 IU/mL with normal ALT), comprising predominantly two subgroups, (I) normal (<ULN) or mildly elevated (<2x ULN) ALT with HBV DNA >=2,000 IU/mL, or (II) elevated ALT (>ULN) with HBV DNA <2,000 IU/mL, with ALT interpreted against ULN 35 U/L (males) and 25 U/L (females) and phase assigned on >=2 ALT and HBV DNA measurements over a 6-12 month period; in adults who are HBsAg-positive, HBeAg-negative, without cirrhosis and in the indeterminate phase so defined, AASLD SUGGESTS antiviral therapy using a shared decision-making approach assessing risks and benefits, and re-evaluating that decision at each follow-up visit if treatment has not been initiated (CONDITIONAL, VERY LOW certainty). Decision-relevant factors include fibrosis stage, age, and sex, e.g. age >40, male sex, and low-normal platelets (<180 k/mm3) favor treatment. (5) DISCONTINUATION, in adults with CHB who are HBeAg-negative, without cirrhosis, with sustained undetectable HBV DNA on nucleos(t)ide analogue therapy, AASLD SUGGESTS NOT withdrawing NA therapy until HBsAg loss (CONDITIONAL, VERY LOW certainty). If a patient nonetheless has a strong desire to stop, shared decision-making applies and ALL of the following must be met: no history of advanced fibrosis/cirrhosis, hepatic decompensation (variceal bleed, ascites, encephalopathy, hepatorenal syndrome), HCC, or extrahepatic HBV complications; if HBeAg-positive at treatment start, HBeAg seroconversion to anti-HBe-positive for >=1 year with undetectable HBV DNA >=2 years; if HBeAg-negative at start, undetectable HBV DNA >=2 years; no HIV or HDV coinfection; quantitative HBsAg <100 IU/mL; and willingness to adhere to frequent monitoring. After stopping, monitor ALT and HBV DNA every 1-3 months for 6 months, then every 3 months for 6-12 months, then every 3-6 months. Restart antivirals IMMEDIATELY if HBV DNA >=10,000 IU/mL (4 log IU/mL) at any time regardless of ALT, OR ALT >=5x ULN regardless of HBV DNA, OR total bilirubin >2.5 mg/dL. (6) HCC SURVEILLANCE (all CONDITIONAL, VERY LOW certainty; modality/interval per AASLD 2023 HCC Practice Guidance), Rec 6: after HBsAg loss, continue surveillance in those with cirrhosis, family history of HCC, men who lost HBsAg after age 40, and women who lost HBsAg after age 50. Rec 7: in HBV-HDV coinfection, surveil adults independent of cirrhosis status; in children, individualize because HCC risk in that population is unknown. Rec 8: in HBV-HIV coinfection, surveil men >=18 years and women >=40 years. Rec 9: in HBV-HCV coinfection, AASLD recommends treating HCV and suggests HCC surveillance per HBV mono-infection criteria. Where a person has more than one coinfection, the surveillance recommendation should follow the coinfection carrying the highest associated risk. The guideline notes that most of its recommendations rest on low or very low certainty evidence and that shared decision-making, not uniform policy, is the intended mode of application.

An elevated alkaline phosphatase should first be confirmed to be of hepatic origin: confirm with an elevated GGT, or use ALP isoenzyme fractionation or 5'-nucleotidase to separate liver from non-hepatic (e.g., bone) sources. GGT should NOT be used as a standalone screening test in the absence of otherwise-abnormal liver chemistries, and GGT is not specific (elevated in >50% of alcohol users without overt liver disease). Patients with an elevated ALP, with or without elevated bilirubin, should be tested for primary biliary cholangitis with an anti-mitochondrial antibody (AMA). Once ALP is confirmed to be of hepatic origin, obtain a liver ultrasound to assess the hepatic parenchyma and bile ducts: biliary dilatation suggests an extrahepatic cause, while a non-dilated biliary system suggests an intrahepatic cause. Patients with an elevated ALP, with or without elevated bilirubin, should also be tested for primary sclerosing cholangitis with cholangiography by MRCP (or ERCP) together with serum IgG4, because some extrahepatic cholestatic disease (e.g., PSC, HIV/AIDS cholangiopathy) may not be visible on ultrasound; a history of cholangitis or of colonic inflammatory bowel disease further raises suspicion but is not a prerequisite for obtaining cholangiography. Liver biopsy is generally not required; about 80% of isolated ALP elevations can be diagnosed from history, physical exam, routine labs, and chest X-ray.