Causes of Hepatitis

1. Viral Hepatitis

Hepatitis A (HAV)

• Transmitted via the fecal-oral route (contaminated food/water)
• Causes acute hepatitis only; does not cause chronic liver disease
• Usually mild and self-limiting; resolves within 6 months
• Vaccine-preventable
• Robbins Pathologic Basis of Disease

Hepatitis B (HBV)

• Transmitted parenterally (blood, sexual contact, mother-to-child)
• Most infections are subclinical; ~5% progress to chronic infection
• Chronic HBV is a major cause of cirrhosis and hepatocellular carcinoma (HCC)
• Affects nearly 300 million people worldwide
• Vaccine-preventable
• Goldman-Cecil Medicine

Hepatitis C (HCV)

• Transmitted mainly via blood (IV drug use, transfusions)
• Acute infection is almost always subclinical
• 80% or more progress to chronic liver disease
• Leading cause of cirrhosis and HCC; now curable with direct-acting antivirals
• Affects nearly 60 million worldwide
• Goldman-Cecil Medicine

Hepatitis D (HDV)

• A defective virus - requires HBV co-infection for replication
• Can occur as co-infection (acute HBV + HDV) or superinfection (chronic HBV + HDV)
• Superinfection can cause rapid decompensation (acute-on-chronic liver failure)
• Robbins Pathologic Basis of Disease

Hepatitis E (HEV)

• Transmitted fecal-orally, endemic in equatorial/developing regions
• Causes acute epidemic disease; generally does not lead to chronic hepatitis - except in immunosuppressed patients
• Particularly severe in pregnancy (high maternal mortality)
• Robbins Pathologic Basis of Disease

Other Viruses (Non-Hepatotropic)

• Epstein-Barr virus (EBV) - infectious mononucleosis
• Cytomegalovirus (CMV)
• Herpes simplex virus (HSV)
• Varicella-zoster virus (VZV)
• Yellow fever virus

2. Alcoholic Hepatitis

• Caused by heavy alcohol consumption leading to toxic liver injury
• Labs typically show: AST <300 U/L, AST:ALT ratio >2, jaundice, leukocytosis
• Can present acutely or as part of chronic alcohol-related liver disease
• Tietz Textbook of Laboratory Medicine

3. Drug-Induced Liver Injury (DILI)

• The most common mechanism is idiosyncratic, immune-mediated hepatocyte injury
• Common offenders: acetaminophen (dose-dependent), NSAIDs, antibiotics (isoniazid, amoxicillin-clavulanate), statins, herbal/complementary products (responsible for ~9% of US cases)
• A temporal relationship between drug exposure and onset of hepatitis is key to diagnosis
• Cholestatic pattern is more common than in viral hepatitis
• Can cause acute or chronic hepatitis; ~15-30% of cases become chronic after stopping the drug
• Tietz Textbook of Laboratory Medicine

4. Autoimmune Hepatitis (AIH)

• Body makes antibodies against liver tissue
• Characterized by: decreased albumin, increased globulins, prolonged aminotransferase elevation
• Diagnosed by exclusion of other causes + presence of autoimmune markers (ANA, anti-smooth muscle antibody)
• Has an acute component in up to 40% of cases
• Tietz Textbook of Laboratory Medicine

5. Metabolic and Genetic Causes

6. Bacterial, Fungal, and Parasitic Infections

• Bacteria: Salmonella typhi (typhoid), Staphylococcus aureus (toxic shock), Treponema pallidum (syphilis), Bartonella henselae (cat-scratch disease)
• Fungi: Histoplasma capsulatum and other disseminated mycoses
• Parasites: malaria, schistosomiasis, amebiasis, echinococcosis, leishmaniasis
• Robbins Pathologic Basis of Disease

7. Ischemic / Vascular Causes

• Budd-Chiari syndrome (hepatic vein obstruction)
• Shock liver (ischemic hepatitis) from severe hypotension or cardiac failure
• Congestive heart failure causing passive hepatic congestion

8. Other / Miscellaneous Causes

• Pregnancy-related: Acute fatty liver of pregnancy, HELLP syndrome
• Toxins: industrial solvents, herbal/alternative preparations
• Celiac disease, hyperthyroidism (cause elevated liver enzymes mimicking hepatitis)
• Lymphoma or carcinoma infiltrating the liver
• Symptom to Diagnosis, 4th Edition

Quick Reference: Mnemonic for Acute Liver Failure Causes (A-F)

From Robbins Pathologic Basis of Disease:

• A - Acetaminophen, Hepatitis A, Autoimmune hepatitis
• B - Hepatitis B
• C - Hepatitis C, Cryptogenic
• D - Drugs/toxins, Hepatitis D
• E - Hepatitis E, Esoteric causes (Wilson disease, Budd-Chiari, lymphoma)
• F - Fatty change (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)

Fulminant Hepatitis (Fulminant Hepatic Failure / Acute Liver Failure)

Definition

• Fulminant hepatic failure: development of hepatic encephalopathy within 8 weeks of onset of symptoms such as jaundice
• Subfulminant hepatic failure: liver disease up to 26 weeks before the onset of encephalopathy
• The essential component in both definitions is hepatic encephalopathy accompanied by coagulopathy (INR ≥1.5)
• ALF affects approximately 2,000-3,000 Americans each year
• Current Surgical Therapy, 14e

• Hyperacute (<7 days from jaundice to encephalopathy) - common with acetaminophen, viral hepatitis A/E, ischemia; highest risk of cerebral edema but better prognosis
• Acute (7-28 days)
• Subacute (>28 days to 26 weeks) - worst prognosis without transplant
• StatPearls / NCBI

Causes

Pathophysiology and Clinical Features

Hepatic Encephalopathy

• Graded I-IV based on mental status
• Driven by hyperammonemia - elevated ammonia causes astrocyte swelling and cerebral edema
• Key distinction from cirrhosis: cerebral edema does NOT develop in chronic liver disease, only in ALF

Cerebral Edema (the leading cause of death)

• Develops in ~80% of patients who reach grade 4 encephalopathy
• Increased intracranial pressure (ICP) reduces cerebral perfusion pressure, causing ischemic brain damage and herniation
• Accounts for >50% of ALF-associated mortality
• Clinical signs on examination only appear after significant edema has developed (too late)
• Head CT is insensitive early; if edema is evident on CT, irreversible brain injury or herniation is likely - at this point, transplantation is contraindicated
• Current Surgical Therapy, 14e

Other Complications

Laboratory Findings

• AST/ALT: markedly elevated, typically 8-50× upper reference limit in viral hepatitis; can be >1000 U/L
• In direct toxic injury (e.g., acetaminophen, ischemia): rapid rise then rapid fall (mirrors enzyme half-lives)
• In immunologic injury (viral, most drugs): gradual rise → plateau → gradual resolution
• ALP: usually <3× URL in acute hepatitis (contrast with cholestatic disease)
• Bilirubin: predominantly direct (conjugated)
• PT/INR: prolonged - reflects loss of hepatic synthetic function (hallmark of severity)
• Glucose: hypoglycemia from impaired gluconeogenesis
• Tietz Textbook of Laboratory Medicine, 7e

Prognosis: King's College Criteria

• pH <7.3, OR
• INR >6.5 AND serum creatinine >3.4 mg/dL

• INR >6.5, OR
• Any 3 of the following:
  • INR >3.5
  • Bilirubin >17.6 mg/dL
  • Age <10 or >40 years
  • Cause: drug toxicity (non-acetaminophen)
  • Time from jaundice to encephalopathy >7 days

Management

Immediate Steps

• Transfer immediately to a liver transplant center - can progress to death rapidly
• ICU admission with meticulous monitoring

Specific Treatments

Managing Cerebral Edema / Raised ICP

• Elevate head of bed (30°)
• Minimize stimulation; use sedation/paralysis
• Mannitol (osmotic therapy) - reduces ICP; note rebound on cessation
• Hypertonic saline - also reduces ICP
• ICP monitoring (controversial - risk of intracranial hemorrhage)
• Lactulose is NOT recommended in ALF (unlike cirrhosis) - has never been shown to improve survival in this setting
• Current Surgical Therapy, 14e; Harrison's, 22e

What Does NOT Work

• Glucocorticoids (ineffective in controlled trials; may increase risk of chronicity in hepatitis B)
• Exchange transfusion, plasmapheresis, extracorporeal liver-assist devices - not proven to enhance survival
• Harrison's Principles of Internal Medicine, 22e

Liver Transplantation

• The only definitive treatment for patients meeting King's College criteria
• Patients are given Status 1 (highest priority) - goal is transplant within 48-72 hours of presentation
• Listing decisions should be made within 24 hours
• Outcomes: 1-year patient survival ~73-80%; 5-year survival ~67-73%
• Contraindicated if cerebral edema is evident on CT (irreversible brain injury already present)
• Mulholland & Greenfield's Surgery, 7e

Special Situations

Fulminant Hepatitis in Pregnancy (Hepatitis E)

• HEV causes particularly severe fulminant hepatitis in pregnant women
• Mortality reported 10-30%, with high rates of fetal loss
• Management includes delivery of the infant and placenta in acute fatty liver of pregnancy/HELLP
• Sherris & Ryan's Medical Microbiology, 8e

Fulminant Hepatitis B

• HBV + HDV superinfection can cause rapid acute-on-chronic decompensation
• Oral antiviral therapy (tenofovir, entecavir) can be used but benefit is limited in late-stage ALF

Fulminant Hepatitis C

• Very rare

Summary