What are the management strategies for Chronic Liver Disease (CLD)?

Management of Chronic Liver Disease

Treat the Underlying Etiology First

The cornerstone of chronic liver disease management is identifying and treating the specific underlying cause to prevent progression to cirrhosis and hepatocellular carcinoma. 1

Viral Hepatitis Management

Chronic Hepatitis B:

• Use first-line agents entecavir 0.5 mg daily, tenofovir disoproxil fumarate 300 mg daily, or peginterferon alfa-2a in patients with elevated ALT and HBV DNA ≥2000 IU/mL. 1, 2, 3
• All cirrhotic patients with detectable HBV DNA require treatment regardless of ALT levels. 1
• For lamivudine-refractory disease or decompensated liver disease, increase entecavir to 1 mg daily. 2
• Monitor HBV DNA and ALT every 3-6 months during therapy; assess for virologic breakthrough and renal function in patients on nucleos(t)ide analogues. 1
• Sustained viral suppression prevents cirrhosis progression and reduces (but does not eliminate) HCC risk—lifelong surveillance remains mandatory. 1

Chronic Hepatitis C:

• Use direct-acting antivirals (DAAs) to achieve sustained viral response in all eligible patients. 1
• Sustained viral response prevents cirrhosis progression but does not eliminate HCC risk in patients with established cirrhosis. 1

Alcohol-Related Liver Disease

Complete and permanent alcohol abstinence is mandatory for all patients with alcoholic liver disease. 1

• Heavy drinking thresholds that must not be exceeded: >4 drinks/day or >14 drinks/week in men; >3 drinks/day or >7 drinks/week in women. 1

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/NAFLD)

Lifestyle modification is the primary treatment, with 7-10% weight loss required to improve steatohepatitis and achieve fibrosis regression. 1

Dietary Interventions:

• Create a 500-1000 kcal/day deficit: typically 1,200-1,500 kcal/day for women and 1,500-1,800 kcal/day for men. 1
• Weight loss must be gradual at 500-1000g per week maximum—rapid weight loss worsens liver disease. 1
• Implement a Mediterranean diet pattern with daily vegetables, fruits, fiber-rich cereals, nuts, fish or white meat, and olive oil—this reduces liver fat even without weight loss. 1
• Eliminate fructose-containing beverages and processed foods. 1
• Replace saturated fats with monounsaturated and polyunsaturated fats, especially omega-3 fatty acids. 1

Exercise Prescription:

• Prescribe 150-300 minutes of moderate-intensity aerobic exercise per week or 75-150 minutes of vigorous-intensity exercise. 1
• Both aerobic and resistance training reduce liver fat; vigorous exercise provides greater benefit for NASH and fibrosis than moderate exercise. 1

Pharmacological Therapy:

• Consider resmetirom if locally approved for non-cirrhotic MASH with significant fibrosis (stage ≥2). 1
• Use incretin-based therapies (semaglutide, tirzepatide) for patients with type 2 diabetes or obesity when indicated. 1
• Use GLP-1 agonists for NASH recovery; avoid sulfonylureas and insulin as they may increase HCC risk. 1
• Bariatric surgery is an option for patients with MASLD and obesity meeting national eligibility criteria—it resolves NASH in 85% of patients at 1 year and improves steatosis, steatohepatitis, and fibrosis. 1

Management of Complications

Hepatic Encephalopathy

Identify and correct precipitating factors first—this resolves up to 90% of cases. 4

• Common precipitating factors: infections, gastrointestinal bleeding, constipation, dehydration, electrolyte disturbances, sedative medications. 4

Pharmacological Management:

• Lactulose is first-line treatment, titrated to achieve 2-3 soft stools per day. 5, 4
• Rifaximin is second-line or additional therapy for patients with recurrent episodes despite lactulose use. 4
• Secondary prophylaxis with lactulose is indicated after the first episode of overt hepatic encephalopathy. 4
• Brain imaging should be done in every patient with CLD and unexplained alteration of brain function to exclude structural lesions. 5

Nutritional Support:

• Address malnutrition present in approximately 75% of patients with hepatic encephalopathy. 4
• Provide moderate hyperalimentation with small, frequent meals throughout the day, including a late-night snack. 4
• Multivitamin supplementation is generally recommended. 4

Portal Hypertension and Variceal Bleeding

Three main goals: prevention of first bleed, control of acute bleeding, and prevention of re-bleeding. 6

• Non-selective β-adrenoceptor antagonists for primary prophylaxis (though not generally recommended in children). 6
• Control bleeding using a stepwise approach from least to most invasive strategies. 6
• Prevention of re-bleeding using bypass operations, with particular enthusiasm for meso-Rex bypass in pediatric population. 6

Ascites and Spontaneous Bacterial Peritonitis

Treatment of mild ascites and peripheral edema:

• Begin with restriction of sodium and water. 6
• Follow with careful diuresis. 6
• Large-volume paracentesis associated with colloid volume expansion in severe cases. 6

Spontaneous bacterial peritonitis:

• Use empiric broad-spectrum antimicrobial therapy after taking appropriate cultures, with changes in therapy after sensitivity testing. 6
• Manage complications of cirrhosis (spontaneous bacterial peritonitis and GI bleeding) according to available guidelines. 5

Hepatorenal Syndrome

Treatment should be initiated early to prevent progression of renal failure. 6

• General supportive measures and management of concomitant complications. 6
• Screen for sepsis and treat with antibiotics. 6
• Use vasopressin analogs (terlipressin). 6
• Renal replacement therapy if needed. 6

Pruritus

Empirical therapies remain standard practice: 6

• Bile acid binding agents. 6
• Phenobarbital. 6
• Ursodeoxycholic acid. 6
• Antihistamines. 6
• Rifampin. 6
• Carbamazepine. 6
• Partial external biliary diversion can be used in refractory cases. 6

Risk Stratification and Surveillance

Use a stepwise approach with FIB-4 score followed by transient elastography to identify patients with advanced fibrosis who require closer monitoring. 1

Case-Finding Strategy:

• Apply in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological hepatic steatosis, particularly with type 2 diabetes or obesity with additional metabolic risk factors. 1
• Manage low-risk patients in the community with lifestyle advice and cardiovascular risk reduction, reassessing with non-invasive tests after 3 years. 1
• Fibrosis progresses in a significant proportion of individuals, so repeated assessment every 1-3 years is required in at-risk patients. 1

Hepatocellular Carcinoma Surveillance:

• Perform 6-monthly ultrasound and AFP measurement for all cirrhotic patients. 1
• Lifelong HCC surveillance is required for cirrhotic patients, even after viral clearance. 1
• Early treatment of underlying liver diseases before progression to cirrhosis is the most effective approach for preventing HCC and liver-related mortality. 1

Management of Cardiometabolic Comorbidities

Use statins for dyslipidemia in all NAFLD patients—they carry no increased risk of serious liver injury and reduce HCC risk by 37%. 1

• Optimize treatment for type 2 diabetes, as patients with or who develop T2DM have higher risk of fibrosis progression. 1
• Assess lipid profile, fasting glucose/HbA1c, waist circumference, and BMI regularly. 1

Bone Disease Management

Bone densitometry should be evaluated in patients with previous fragility fractures, those treated with corticosteroids, and before liver transplantation. 5

• In patients with normal BMD, repeat DEXA after 2-3 years. 5
• In cholestatic patients with more than one risk factor for osteoporosis and those with recently initiated high-dose corticosteroid therapy, repeat DEXA in approximately one year. 5
• Patients with PBC with a lumbar or proximal femur T-score <−1.5 have high risk for vertebral fracture and should receive specific therapy. 5

Nutritional and Lifestyle Interventions:

• Provide supplements of calcium (1,000–1,500 mg/d) and 25-hydroxy-vitamin D (400–800 IU/d or 260 μg every 2 weeks). 5
• Recommend physical activity, particularly exercises designed to improve spine mechanics. 5
• Discontinue alcohol and tobacco use. 5
• Minimize corticosteroids whenever possible. 5

Vaccination and Prevention

Vaccinate against hepatitis B: all infants (universal childhood immunization), high-risk adults, and exposed individuals. 1

• Vaccinate against hepatitis A: all anti-HAV negative patients with chronic liver disease. 1
• Hepatitis B vaccination reduces HCC risk and is recommended for all newborns and high-risk groups. 1

Follow-Up After Hepatic Encephalopathy

Discharge Planning:

• Confirm neurological status before discharge and determine extent of deficits attributable to HE versus other neurological comorbidities. 5
• Inform caregivers that neurological status may change once acute illness has settled and medication requirements could change. 5

Recognize Precipitating and Risk Factors:

• Plan future clinical management according to: (1) potential for improvement of liver function (e.g., acute alcoholic hepatitis, autoimmune hepatitis, hepatitis B), (2) presence of large portosystemic shunts (which may be suitable for occlusion), and (3) characteristics of precipitating factors. 5

Patient and Family Education:

• Effects of medication (lactulose, rifaximin) and potential side effects (e.g., diarrhea). 5
• Importance of adherence. 5
• Early signs of recurring HE. 5
• Actions to take if recurrence (e.g., anticonstipation measures for mild recurrence and referral to general practitioner or hospital if HE with fever). 5

Monitoring:

• Monitor neurological manifestations in patients with persisting HE to adjust treatment and in patients with previous HE to investigate presence and degree of minimal or covert HE or signs of recurring HE. 5
• Motor assessment should include evaluation of gait and walking and consider risk of falls. 5

Socioeconomic Considerations:

• Address decline in work performance, impairment in quality of life, and increased risk of accidents. 5
• Patients often require economic support and extensive care from public social support system. 5

Renal Function Monitoring

In patients with renal impairment on entecavir, adjust dosing based on creatinine clearance. 2

• CrCl 30 to <50 mL/min: 0.5 mg every 48 hours (usual dose) or 0.5 mg once daily (lamivudine-refractory). 2
• CrCl 10 to <30 mL/min: 0.5 mg every 72 hours (usual dose) or 1 mg every 72 hours (lamivudine-refractory). 2
• CrCl <10 mL/min or hemodialysis/CAPD: 0.5 mg every 7 days (usual dose) or 1 mg every 7 days (lamivudine-refractory). 2

Monitor for lactic acidosis and severe hepatomegaly with steatosis—suspend treatment if clinical or laboratory findings suggest lactic acidosis or pronounced hepatotoxicity. 2

Common Pitfalls to Avoid

• Do not rely exclusively on ammonia levels for diagnosis of hepatic encephalopathy—they do not provide diagnostic, prognostic, or staging value. 4
• Do not fail to seek precipitating factors in hepatic encephalopathy, which cause 90% of cases. 4
• Do not use rapid weight loss strategies in MASLD—gradual weight loss at 500-1000g per week maximum is essential as rapid weight loss worsens liver disease. 1
• Do not discontinue HCC surveillance after achieving sustained viral response in cirrhotic patients—lifelong surveillance remains mandatory. 1
• Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, as severe acute exacerbations have been reported. 2