Prescribing in Chronic Liver Disease

Chronic liver disease is any liver injury lasting more than 6 months, ranging from steatotic liver disease with normal synthetic function to decompensated cirrhosis. Prescribing risk tracks the degree of hepatic dysfunction and portal hypertension, not the cause or the transaminase level. No single laboratory value predicts hepatic drug clearance the way creatinine clearance predicts renal clearance.

Spectrum. Non-cirrhotic disease (metabolic dysfunction associated steatotic liver disease, chronic hepatitis B or C, alcohol-related liver disease, autoimmune and cholestatic disease) usually alters drug handling little. Cirrhosis, especially decompensated, alters it substantially.

Staging tools. Child-Pugh class (A 5 to 6, B 7 to 9, C 10 to 15 points) is the basis of most product label adjustments. MELD predicts mortality but is not validated for dosing.

Transaminases. ALT and AST reflect injury, not function. Bilirubin, albumin, INR, ascites and encephalopathy are the markers that predict impaired drug handling.

Key risks. Reduced metabolism of drugs cleared by the liver, raised free fraction of highly protein-bound drugs, increased sensitivity of the brain to sedatives, renal vulnerability to nephrotoxins, and additive hepatotoxicity.

Renal function. Creatinine overestimates glomerular filtration in sarcopenia and cholestasis. Where accuracy matters, use cystatin C based estimates or measured clearance.

Core rule. Prefer drugs with renal elimination, a wide therapeutic index, no active hepatic metabolites and no intrinsic hepatotoxicity. Use the lowest effective dose and the fewest agents.

Generally suitable with usual care. - Paracetamol at a reduced daily ceiling of 2 to 3 g. - Beta-lactams such as amoxicillin and ceftriaxone. - Lorazepam or oxazepam when a benzodiazepine is unavoidable, because glucuronidation is relatively preserved. - Statins in compensated disease, which are safe and advised for cardiovascular risk. - Insulin when glycaemic control is needed in advanced disease.

Avoid or use with specialist input. - Non-steroidal anti-inflammatory drugs once portal hypertension or ascites is present. - Aminoglycosides, given the high risk of acute kidney injury. - Long-acting benzodiazepines and sedating antihistamines. - Drugs with known idiosyncratic hepatotoxicity when a safer alternative exists, for example co-amoxiclav, nitrofurantoin long term, ketoconazole orally.

Hepatitis B reactivation. Before rituximab, other anti-CD20 agents, high-dose corticosteroids, chemotherapy or Janus kinase inhibitors, test HBsAg and anti-HBc. Give prophylaxis to HBsAg positive patients and to anti-HBc positive patients on high-risk agents such as rituximab.

Hepatitis C direct-acting antivirals. Check every co-prescribed drug for interactions before starting, particularly amiodarone (serious bradycardia with sofosbuvir), statins, antiepileptics, acid suppressants and rifampicin.

Vaccination. Hepatitis A and B (if non-immune), pneumococcal, annual influenza and COVID-19 vaccines are advised in all chronic liver disease.

Non-cirrhotic disease. Most drugs need no adjustment when bilirubin, albumin and INR are normal. Apply label hepatic restrictions where they are based on transaminase thresholds, for example pioglitazone and some antivirals.

Cirrhosis. Use Child-Pugh based label advice. Where none exists, start high extraction oral drugs at about 50% of the usual dose, and extend dosing intervals for low extraction drugs.

Hepatitis B prophylaxis regimens.

Weight. In ascites, calculate weight-based doses from estimated dry weight.

Special groups. - Pregnancy: tenofovir disoproxil is the antiviral of choice; entecavir is not advised. Intrahepatic cholestasis of pregnancy is treated with ursodeoxycholic acid 10 to 15 mg/kg daily in 2 divided doses. - Breastfeeding: tenofovir disoproxil is compatible. - Older adults: reduced hepatic blood flow adds to disease effect; start low. - East Africa: hepatitis B is highly prevalent, and herbal and traditional remedies are a frequent unrecognised cause of worsening liver tests; ask specifically.

Baseline. ALT, AST, alkaline phosphatase, bilirubin, albumin, INR, platelet count, creatinine, sodium, and hepatitis B and C serology.

Monitoring. Repeat liver tests 2 to 4 weeks after starting any drug with hepatotoxic potential, then at intervals set by that drug. Where baseline ALT is already raised, judge change against the patient’s own baseline rather than the upper limit of normal.

Stopping thresholds. Stop a suspected culprit when: - ALT exceeds 3 times the upper limit of normal (or 3 times baseline) with symptoms or jaundice. - ALT exceeds 5 times the upper limit of normal (or 5 times baseline) without symptoms. - Bilirubin exceeds 2 times the upper limit of normal with any ALT rise, or INR rises.

Referral and escalation. Refer to hepatology for new jaundice, coagulopathy, encephalopathy, or any drug-induced liver injury with bilirubin rise. Seek specialist advice before immunosuppression in hepatitis B carriers and before starting narrow therapeutic index drugs in Child-Pugh B or C.