Liver Diseases - Clinical Reference

1. Overview & Classification

2. Clinical Features of Liver Disease

Symptoms

• Fatigue, anorexia, right upper quadrant discomfort
• Jaundice, dark urine, pale stools (cholestatic pattern)
• Pruritus (especially in cholestatic disease)

Physical Examination Signs

• Icterus (jaundice detectable when bilirubin >2.5 mg/dL)
• Hepatomegaly (firmness and nodularity suggest cirrhosis)
• Splenomegaly (suggests portal hypertension/cirrhosis)
• Spider angiomata (arms, face, upper torso - fill from center outward)
• Palmar erythema

• Muscle wasting, ascites, peripheral edema
• Dilated abdominal veins (caput medusae)
• Hepatic fetor, asterixis
• Mental confusion → stupor → coma (hepatic encephalopathy)
• Gynecomastia, testicular atrophy (hyperestrogenemia in alcoholic cirrhosis)

3. Cirrhosis

Pathophysiology

Complications

Portal Hypertension

• Results from increased sinusoidal vascular resistance (fixed: fibrosis + nodules; functional: vasoconstriction from intrahepatic NO deficiency) plus increased portal venous inflow from splanchnic vasodilation
• Threshold: hepatic venous pressure gradient (HVPG) >10-12 mmHg for variceal formation; >12 mmHg for ascites formation

Varices and Variceal Hemorrhage

• Gastroesophageal varices form via dilation of coronary and gastric veins
• Variceal rupture risk is proportional to variceal diameter x intravariceal pressure / wall thickness (LaPlace's law)
• Variceal hemorrhage is one of the most dangerous complications of portal hypertension

Ascites

• Secondary to sinusoidal hypertension and sodium retention driven by splanchnic vasodilation and increased NO production
• Progressive: leads to hyponatremia, refractory ascites, and hepatorenal syndrome (HRS)

Spontaneous Bacterial Peritonitis (SBP)

• Infection of ascitic fluid without a hollow viscus perforation
• Mechanism: bacterial translocation from intestinal lumen to mesenteric lymph nodes, facilitated by impaired Kupffer cell function (due to portosystemic shunting)
• Diagnosed by ascitic PMN count >250 cells/mm³

Hepatic Encephalopathy (HE)

• Results from both portal hypertension (portosystemic shunting) and liver insufficiency
• Spectrum: subtle sleep/personality changes → confusion/disorientation → stupor → coma

4. Viral Hepatitis

Chronic Hepatitis B

• Defined as HBsAg persistence for ≥6 months
• Phases: immune tolerant → immune active → inactive carrier → reactivation
• HBV DNA PCR useful for diagnosing early infection (before HBsAg appears), distinguishing active vs. inactive infection, and monitoring treatment response
• Treatment: nucleos(t)ide analogues (tenofovir, entecavir) - viral suppression but rarely cure

Chronic Hepatitis C

• Most common cause of chronic liver disease in many regions
• HCV RNA PCR for confirmation; genotype guides treatment duration
• Treatment: direct-acting antivirals (DAAs) achieve >95% sustained virologic response (SVR = functional cure)

5. Steatotic Liver Disease

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

• Most common chronic liver disease worldwide, affecting ~30% of adults
• Spectrum: simple steatosis → metabolic dysfunction-associated steatohepatitis (MASH/NASH) → fibrosis → cirrhosis → HCC
• Diagnosis: steatosis on imaging or histology, after exclusion of excessive alcohol use
• Histology: macrovesicular steatosis affecting ≥5% of hepatocytes; NASH requires additional ballooning degeneration and lobular inflammation
• Liver biopsy required to distinguish NASH from simple steatosis
• Risk factors: obesity, type 2 diabetes, metabolic syndrome, dyslipidemia
• Management: weight loss (≥7-10% body weight), exercise, treatment of metabolic comorbidities; resmetirom (thyroid receptor-beta agonist) is the first FDA-approved drug for MASH with fibrosis (2024); semaglutide updated into AASLD guidance for MASH in November 2025

Alcoholic/Alcohol-Associated Liver Disease (ALD)

• Spectrum: alcoholic fatty liver (steatosis) → alcoholic hepatitis → alcoholic cirrhosis
• Alcoholic hepatitis: acute presentation with jaundice, fever, tender hepatomegaly, leukocytosis; AST:ALT ratio typically >2:1
• Maddrey Discriminant Function (DF) >32 indicates severe disease - consider corticosteroids
• Abstinence is the cornerstone of all treatment

6. Acute Liver Failure (ALF)

Causes (by frequency in Western countries)

1. Acetaminophen overdose (most common in US/UK)
2. Hepatitis A, B, C, D, E
3. Drug-induced liver injury (DILI)
4. Autoimmune hepatitis
5. Wilson disease
6. Budd-Chiari syndrome

Key Clinical Features

• Rapid onset of encephalopathy + coagulopathy (INR >1.5)
• Cerebral edema (life-threatening in acute vs. chronic liver failure)
• Multi-organ failure: renal failure, respiratory failure, hypoglycemia, coagulopathy

Management Priorities

• Acetaminophen: N-acetylcysteine (NAC) - works even in late presentation
• Supportive ICU care: intracranial pressure monitoring, lactulose/rifaximin for HE, vasopressors, renal replacement therapy
• Liver transplantation: definitive therapy; King's College Criteria guide listing decision

7. Autoimmune & Cholestatic Diseases

Autoimmune Hepatitis (AIH)

• Predominantly in women; elevated IgG, positive ANA/ASMA (Type 1) or anti-LKM-1 (Type 2)
• Treatment: prednisolone ± azathioprine; remission in >80%

Primary Biliary Cholangitis (PBC)

• Anti-mitochondrial antibody (AMA) positive in >90%
• Granulomatous destruction of small intrahepatic bile ducts
• Treatment: ursodeoxycholic acid (UDCA); obeticholic acid for inadequate UDCA response

Primary Sclerosing Cholangitis (PSC)

• Strong association with inflammatory bowel disease (especially ulcerative colitis)
• Multifocal strictures of intra- and extrahepatic bile ducts on MRCP ("beaded" appearance)
• Risk of cholangiocarcinoma (10-15% lifetime risk)
• No effective medical therapy; liver transplantation for end-stage disease

8. Key Laboratory Investigations

9. Liver Transplantation

• Harrison's Principles of Internal Medicine, 22E (2025)
• Goldman-Cecil Medicine, 27th ed.
• Robbins, Cotran & Kumar Pathologic Basis of Disease
• Yamada's Textbook of Gastroenterology, 7th ed.
• AASLD Practice Guidance on MASLD (2023, updated 2025) - includes November 2025 semaglutide update and 2024 resmetirom approval
• EASL Clinical Practice Guidelines - covers HBV, HCC, autoimmune hepatitis, liver transplantation