Alcoholic Liver Disease (ALD) - Definition

The Spectrum of ALD

1. Alcoholic fatty liver (steatosis) - The earliest and most common change. Perivenular hepatocytes develop large macrovesicular fat vacuoles. This is reversible with abstinence.
2. Alcoholic hepatitis - An acute inflammatory injury superimposed on steatosis or fibrosis. The histological hallmarks of acute sclerosing hyaline necrosis in alcoholic hepatitis are:
   • Hydropic hepatocytes containing Mallory hyaline bodies (eosinophilic ropy cytoplasmic material)
   • Neutrophil infiltration around damaged cells
   • Perivenular (zone 3) inflammation and sclerosis of terminal hepatic venules
   • Sinusoidal collagenosis
3. Alcoholic fibrosis/cirrhosis - The end stage. Three progressive patterns of fibrosis are seen:
   • Portal and perivenular fibrosis forming fibrous septa → cirrhosis with small regenerative nodules
   • Diffuse interstitial fibrosis encircling individual hepatocytes without parenchymal regeneration
   • Progressive perivenular fibrosis with dense scar-like collagen in zone 3 with minimal portal fibrosis

The diagnosis of ALD requires documentation of chronic alcohol abuse. Although acute cellular damage implies recent heavy drinking, these changes are typically seen in patients with a long history of alcohol abuse. - Yamada's Textbook of Gastroenterology, 7th ed.; Schwartz's Principles of Surgery, 11th ed.

Chronic Liver Disease (CLD) - Definition

Key Features

• The term encompasses any etiology of sustained liver injury lasting >6 months
• Lethargy and weakness are common early features, irrespective of aetiology, and often precede clinical jaundice
• In advanced disease, impaired glucuronyl conjugation of bilirubin and reduced biliary excretion of conjugated bilirubin occurs
• CLD is the third leading cause of premature death in the UK, and deaths have risen by 400% since 1970
• 75% of patients present with late-stage disease; 90% of cases are potentially preventable

Common Causes of CLD

• Bailey and Love's Short Practice of Surgery, 28th ed.; Sleisenger and Fordtran's GI and Liver Disease; Schwartz's Principles of Surgery, 11th ed.

Relationship Between ALD and CLD

Diagnostic Criteria for Atypical HUS (aHUS)

Step 1 - Confirm the TMA Triad

Comprehensive Clinical Nephrology, 7th ed.; Robbins Pathologic Basis of Disease

Step 2 - Exclude Other Causes of TMA (Mandatory)

• Stool culture and PCR for E. coli O157:H7 and other Shiga toxin (Stx)-producing E. coli
• Serum anti-Stx antibodies
• Bloody diarrheal prodrome strongly suggests STEC-HUS
• Approximately 90% of HUS cases are STEC; ~10% are atypical

• Measure ADAMTS13 activity: <10% confirms TTP; a normal or mildly reduced level supports aHUS
• ADAMTS13 testing is the single most important step to distinguish TTP from aHUS
• TTP: more severe thrombocytopenia, less severe AKI, CNS features dominate
• aHUS: severe AKI predominates; extrarenal manifestations in only 10-20%

• Malignant hypertension
• Autoimmune diseases (SLE, antiphospholipid syndrome)
• Pregnancy-related TMA (HELLP syndrome, postpartum TMA)
• Infections (HIV, pneumococcal HUS via neuraminidase)
• Malignancy
• Drugs (calcineurin inhibitors, quinine, chemotherapy, antiplatelet agents)
• Post-transplant TMA
• Cobalamin C deficiency (in children)

Comprehensive Clinical Nephrology, 7th ed. (Fig. 30.1 diagnostic algorithm)

Step 3 - Identify Complement Dysregulation (Confirmatory)

• C3: Low in ~50% of aHUS patients (C3 consumption by unchecked alternative pathway activation); C4 is typically normal (distinguishes from classical pathway activation)
• C4: Normal
• Elevated C3 degradation products (C3d, C3bBbP)

• Present in ~5-10% of patients (acquired form of aHUS)
• Almost exclusively associated with CFHR1 and CFHR3 gene deletion
• Nearly all patients with anti-CFH antibodies develop disease before age 16

NKF Primer on Kidney Diseases, 8th ed.; Comprehensive Clinical Nephrology, 7th ed.

Summary Diagnostic Algorithm

TMA Triad confirmed (MAHA + thrombocytopenia + AKI)
        ↓
STEC testing negative (stool PCR/culture, serology)
        ↓
ADAMTS13 activity >10% (excludes TTP)
        ↓
No secondary cause identified
        ↓
Complement studies: Low C3, normal C4, elevated C3b products
        ↓
Genetic panel: CFH, MCP, CFI, C3, CFB, THBD mutations
Anti-CFH antibody testing
        ↓
DIAGNOSIS: aHUS (primary complement-mediated)

Important Practical Points

• Treat before genetic results: Eculizumab (anti-C5 monoclonal antibody) or plasma exchange should be started within 24 hours of clinical diagnosis - do not wait weeks for genetic results
• ~50% of patients with primary aHUS and genetic risk factors require a trigger (infection, pregnancy, surgery, drugs) to manifest disease
• Complement gene mutations may also be found in some secondary HUS cases, blurring classification boundaries
• ~20-30% of aHUS cases have no identifiable complement mutation - diagnosis remains clinical after exclusion
• Mortality/progression to ESKD before eculizumab era: 50-70% of patients with CFH/CFI/C3/CFB/THBD mutations; outcome best with MCP (CD46) mutations (80% remained dialysis-free)

Comprehensive Clinical Nephrology, 7th ed.; NKF Primer on Kidney Diseases, 8th ed.; Robbins, Cotran & Kumar Pathologic Basis of Disease