GI Pharmacology · Module 7 of 8

Liver Part 2: ALD, MASLD/MASH, Cholestatic Disease, and Hepatic Encephalopathy

Corticosteroids in alcoholic hepatitis · MASH pharmacotherapy · UDCA and obeticholic acid · Lactulose and rifaximin

Alcoholic hepatitis severity: Maddrey discriminant function (DF) = 4.6 × (PT − control PT) + bilirubin μmol/L ÷ 17.1; DF ≥32 = severe (28-day mortality >30–35% without treatment) → treat with prednisolone 40 mg daily ×28 days if no active infection or HBV co-infection; exclude infection and check HBV before every course; assess Lille score at day 7 (incorporates bilirubin change) — Lille >0.45 = non-responder; stop prednisolone and evaluate for transplant; STOPAH trial: prednisolone reduced 28-day mortality but benefit not maintained at 90 days or 1 year; pentoxifylline: no longer recommended (STOPAH: no mortality benefit); abstinence is the most important long-term determinant of survival; DF <32 → supportive care and abstinence only.
MASLD/MASH (formerly NAFLD/NASH): lifestyle modification (7–10% weight loss → histological improvement; >10% → fibrosis regression) is first-line and most effective; resmetirom (thyroid hormone receptor-beta agonist, liver-targeted) = first FDA-approved MASH drug (March 2024): THR-beta stimulates hepatic fatty acid oxidation, reduces triglycerides; spares heart (THR-alpha mediated); approved for non-cirrhotic MASH with fibrosis stage F2–F3 (MAESTRO-MASH trial); vitamin E 800 IU daily: non-diabetic MASH; improves steatosis/inflammation but not fibrosis; pioglitazone (PPAR-gamma agonist): MASH with type 2 diabetes; GLP-1 receptor agonists (semaglutide): improving MASH evidence (ESSENCE trial) but not yet liver-specific FDA indication.
Primary biliary cholangitis (PBC) treatment is sequential: step 1 — UDCA 13–15 mg/kg/day (first-line for all patients): replaces toxic hydrophobic bile acids, stimulates bile salt export pump, membrane stabilization, immunomodulation; assess biochemical response at 12 months (Paris II criteria: ALP <1.67× ULN + normal bilirubin); 30–40% have inadequate response; step 2 (inadequate responders) — obeticholic acid (FXR agonist: suppresses CYP7A1 → reduces bile acid synthesis + stimulates export) or bezafibrate (PPAR-alpha agonist, off-label); obeticholic acid causes pruritus in majority; manage with cholestyramine; contraindicated in decompensated cirrhosis; primary sclerosing cholangitis: no proven pharmacological disease-modifying therapy.
Hepatic encephalopathy (HE): ammonia produced by colonic bacterial metabolism of nitrogenous compounds bypasses liver via portosystemic shunts → crosses BBB → astrocyte glutamine accumulation → cerebral edema; first step = always identify and correct precipitant (GI bleeding, infection, constipation, hypokalemia, hyponatremia, sedatives); lactulose (non-absorbable disaccharide): fermented to short-chain fatty acids → lowers colonic pH → traps NH₃ as NH₄⁺ (poorly absorbed); target 2–3 soft stools/day; over-purging → dehydration/hyponatremia → worsens HE; rifaximin 550 mg BID added to lactulose for secondary prophylaxis after first HE episode: reduces recurrence by 58%, hospitalizations by 50% (Bass et al.).
HE additional considerations: do NOT restrict dietary protein (1.2–1.5 g/kg/day required to prevent sarcopenia; sarcopenia worsens HE prognosis); vegetable and dairy protein preferred over animal-derived; zinc supplementation in deficient patients (zinc required for urea cycle enzymes); neomycin no longer recommended (nephrotoxicity, ototoxicity with long-term use despite minimal systemic absorption); rifaximin minimally absorbed (<0.4%) — intraluminal action, well tolerated, no meaningful systemic antibiotic resistance contribution.

ALD = alcoholic liver disease · ALP = alkaline phosphatase · BBB = blood-brain barrier · BID = twice daily · CYP7A1 = cholesterol 7-alpha hydroxylase · DF = discriminant function · FXR = farnesoid X receptor · GLP-1 = glucagon-like peptide-1 · HBV = hepatitis B virus · HE = hepatic encephalopathy · MASLD = metabolic dysfunction-associated steatotic liver disease · MASH = metabolic dysfunction-associated steatohepatitis · OCA = obeticholic acid · PBC = primary biliary cholangitis · PPAR = peroxisome proliferator-activated receptor · PSC = primary sclerosing cholangitis · PT = prothrombin time · THR-beta = thyroid hormone receptor-beta · UDCA = ursodeoxycholic acid · ULN = upper limit of normal

Alcoholic Liver Disease: Severity Scoring and Treatment

Maddrey Discriminant Function

Treatment Threshold ≥32

DF = 4.6 × (PT − control PT in seconds) + serum bilirubin μmol/L ÷ 17.1
DF ≥32: severe alcoholic hepatitis; 28-day mortality >30–35% without treatment → consider prednisolone if no contraindications
DF <32: supportive care, nutritional support (35–40 kcal/kg/day), abstinence; corticosteroids not indicated
Alternative scores: MELD, Glasgow Alcoholic Hepatitis Score
Abstinence from alcohol is the single most important long-term determinant of survival regardless of pharmacological treatment

Prednisolone Treatment

40 mg Daily × 28 Days — With Conditions

Reduces 28-day mortality in DF ≥32 alcoholic hepatitis (meta-analyses); benefit not maintained at 90 days or 1 year (STOPAH)
Exclude active infection before starting (spontaneous bacterial peritonitis, UTI, sepsis: immunosuppression worsens outcomes in active infection)
Exclude HBV co-infection (corticosteroids may trigger HBV reactivation)
Assess Lille score at day 7: Lille >0.45 = non-responder → stop prednisolone; evaluate for liver transplantation
Pentoxifylline: no longer recommended (STOPAH trial: no survival benefit vs. placebo at any time point)

MASLD / MASH: Treatment Hierarchy

First Line — All Patients

Lifestyle Modification

7–10% sustained weight loss → histological improvement in steatosis, inflammation, and ballooning in majority
>10% weight loss → fibrosis regression in a substantial proportion
Most effective single intervention available; challenge is long-term adherence (most patients regain weight within 2–5 years and histological gains reverse)
Target: caloric restriction + physical activity; no specific macronutrient composition mandated

First FDA-Approved MASH Drug (March 2024)

Resmetirom

Thyroid hormone receptor-beta (THR-beta) agonist — liver-targeted; stimulates hepatic fatty acid oxidation, reduces triglyceride synthesis and secretion, improves insulin sensitivity
No cardiac adverse effects (cardiac effects of thyroid hormone are mediated by THR-alpha, not THR-beta; resmetirom spares heart)
Approved: non-cirrhotic MASH with fibrosis stage F2–F3; 80 mg or 100 mg daily
MAESTRO-MASH phase 3 trial: superior MASH resolution without worsening fibrosis vs. placebo; fibrosis improvement by ≥1 stage

Selected Patients

Vitamin E, Pioglitazone, GLP-1 Agonists

Vitamin E 800 IU daily: non-diabetic non-cirrhotic MASH; PIVENS trial: improves steatosis/inflammation/ballooning; does NOT improve fibrosis; concerns about all-cause mortality and prostate cancer at high doses limit long-term use
Pioglitazone (PPAR-gamma agonist): MASH with type 2 diabetes; improves hepatic insulin sensitivity and steatohepatitis; weight gain, fluid retention, heart failure risk, bladder cancer risk
GLP-1 receptor agonists (semaglutide): improving evidence in MASH (ESSENCE trial: MASH resolution + fibrosis improvement); not yet liver-specific FDA indication; increasingly used in concurrent T2DM or obesity

Primary Biliary Cholangitis: Sequential Treatment

Agent	Mechanism	Role	Key Caution / Note
UDCA 13–15 mg/kg/day	Replaces toxic hydrophobic bile acids in enterohepatic circulation; activates bile salt export pump; membrane stabilization; immunomodulation	First-line for ALL PBC patients; slows fibrosis, improves biochemistry, reduces liver-related death in long-term studies	Assess biochemical response at 12 months (Paris II: ALP <1.67× ULN + normal bilirubin); 30–40% have inadequate response → add second-line agent
Obeticholic acid (OCA)	FXR agonist: suppresses CYP7A1 (rate-limiting step in bile acid synthesis) + stimulates hepatic bile acid export	Add-on for inadequate UDCA responders (POISE trial: significant ALP reduction)	Pruritus in majority of patients — manage with cholestyramine or rifampicin; contraindicated in decompensated cirrhosis (can worsen hepatic function)
Bezafibrate	PPAR-alpha agonist: modulates bile acid metabolism and nuclear receptor signaling	Off-label second-line add-on; alternative to OCA; better tolerated pruritus profile (BEZURSO trial: significant ALP + pruritus improvement)	Off-label in most markets; monitor renal function and creatine kinase; combination with statins may increase myopathy risk

Hepatic Encephalopathy: Acute Treatment and Secondary Prophylaxis

Lactulose — Acute and Maintenance

Trap Ammonia as NH₄⁺ in Colon

First step always: identify and correct precipitant (GI bleeding, infection, constipation, hypokalemia, hyponatremia, sedative use, portal vein thrombosis) — correcting precipitant alone often resolves mild–moderate HE
Mechanism: fermented by colonic bacteria to short-chain fatty acids → lowers colonic pH → NH₃ → NH₄⁺ (trapped, poorly absorbed); also shifts flora toward non-urease-producing species
Target: 2–3 soft stools per day (adequate drug delivery without over-purging)
Over-purging → dehydration and hyponatremia → worsens encephalopathy; titrate carefully
Lactulose enema if oral route not feasible

Rifaximin — Secondary Prophylaxis

Add to Lactulose After First HE Episode

550 mg BID added to background lactulose; reduces breakthrough HE recurrence by 58% and HE-related hospitalization by 50% (Bass et al., pivotal RCT)
Minimally absorbed (<0.4%): intraluminal action against ammonia-generating bacteria; well tolerated; no significant systemic adverse effects
Indicated for secondary prophylaxis after first HE episode; typically added when lactulose alone fails to prevent recurrence
Do NOT restrict dietary protein: 1.2–1.5 g/kg/day required; protein restriction worsens sarcopenia and paradoxically worsens HE prognosis
Consider zinc supplementation in deficient patients (zinc required as cofactor for urea cycle enzymes)
Neomycin: no longer recommended for HE — nephrotoxicity and ototoxicity with long-term use

Critical Rules — Alcoholic Hepatitis and Hepatic Encephalopathy

Alcoholic hepatitis: never start prednisolone without first excluding active infection and HBV co-infection. Immunosuppression in the presence of occult sepsis or HBV substantially worsens outcomes. Screen with blood cultures, urinalysis, and HBV serology before every corticosteroid course. Assess the Lille score at day 7 — do not continue prednisolone past day 7 in non-responders (Lille >0.45). Pentoxifylline provides no survival benefit and is no longer recommended.

Hepatic encephalopathy: the first priority is precipitant identification and correction — treating the precipitant alone resolves mild to moderate HE in many patients. Do not restrict dietary protein in patients with cirrhosis; protein restriction is now known to worsen sarcopenia and increase HE risk. Avoid over-purging with lactulose (target 2–3 stools per day); diarrhea-induced dehydration and hyponatremia both worsen encephalopathy. For obeticholic acid: pruritus management must be planned proactively at prescription initiation, not reactively after patients discontinue the drug.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Gastrointestinal Pharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
Thursz MR et al.	Prednisolone or pentoxifylline for alcoholic hepatitis (STOPAH trial)	N Engl J Med. 2015;372(17):1619–1628
Mathurin P et al.	Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis	Gut. 2011;60(2):255–260
Harrison SA et al.	Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis (MAESTRO-MASH)	N Engl J Med. 2023;390(6):497–509
Nevens F et al.	A placebo-controlled trial of obeticholic acid in primary biliary cholangitis (POISE)	N Engl J Med. 2016;375(7):631–643
Corpechot C et al.	A placebo-controlled trial of bezafibrate in primary biliary cholangitis	N Engl J Med. 2018;378(23):2171–2181
Bass NM et al.	Rifaximin treatment in hepatic encephalopathy	N Engl J Med. 2010;362(12):1071–1081
Vilstrup H et al.	Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the AASLD and EASL	Hepatology. 2014;60(2):715–735
Lindor KD et al.	Primary biliary cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases	Hepatology. 2019;69(1):394–419