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Hepatitis - Pathology

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Overview

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The Hepatotropic Viruses - Comparison

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Hepatitis A Virus (HAV)

• Nonenveloped, positive-strand RNA picornavirus (genus Hepatovirus)
• Transmission: fecal-oral route - contaminated water/food, shellfish, infected food handlers
• Incubation: 2-6 weeks; shed in stool 2-3 weeks before and 1 week after jaundice onset
• Course: self-limited; does NOT cause chronic hepatitis; fulminant hepatitis in ~0.1%
• HAV is not cytopathic - injury is mediated by cytotoxic CD8+ T cells
• Serology: IgM anti-HAV = acute infection marker; IgG anti-HAV = past infection/immunity (persists lifelong)

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Hepatitis B Virus (HBV)

• Member of Hepadnaviridae; partially double-stranded circular DNA (~3200 nucleotides)
• Four key proteins encoded:
  • HBcAg - nucleocapsid core protein (stays in hepatocytes)
  • HBeAg - secreted precore polypeptide; marker of active replication
  • HBsAg - envelope glycoprotein; massive quantities secreted (non-infective particles); marker of infection
  • HBx protein - required for replication; may transactivate cellular growth genes (role in HCC)
  • Pol - DNA polymerase + reverse transcriptase (target of antiviral drugs); genome replicates via DNA→RNA→DNA
• Epidemiology: 2 billion infected worldwide; 250 million chronic infections; 75% of carriers in Asia/Western Pacific
• Transmission: perinatal (high-prevalence regions), horizontal child-to-child (intermediate), sexual/IV drug use (low-prevalence)

Outcomes of HBV infection:

1. Acute hepatitis with recovery and viral clearance
2. Nonprogressive chronic hepatitis
3. Progressive chronic disease → cirrhosis
4. Fulminant hepatitis with massive liver necrosis
5. Asymptomatic "healthy" carrier state

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Hepatitis C Virus (HCV)

• Enveloped, positive-strand RNA flavivirus
• High chronicity rate (~80%) - the major cause of chronic viral hepatitis globally
• Transmission: primarily parenteral (IV drug use, transfusions before 1992 screening); sexual and perinatal transmission less efficient than HBV
• HCV has high genetic variability due to error-prone RNA replication → immune evasion → chronicity
• Associated with cryoglobulinemia (~35% of chronic HCV) and membranoproliferative glomerulonephritis

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Hepatitis D Virus (HDV)

• "Delta agent" - defective RNA virus; requires HBV (uses HBsAg as its envelope) for infection
• Two patterns:
  • Coinfection (HDV + HBV simultaneously): usually self-limiting; higher acute liver failure risk in IV drug users
  • Superinfection (HDV on chronic HBV carrier): >80% progress to chronic HDV; accelerates cirrhosis and HCC
• Affects ~15 million people worldwide; highest prevalence in Amazon basin, Africa, Middle East, Southern Italy
• Prevention: HBV vaccination protects against HDV (since HDV cannot exist without HBV)

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Hepatitis E Virus (HEV)

• Enterically transmitted, waterborne; ssRNA hepevirus
• Zoonotic reservoir: pigs, monkeys, cats, dogs
• Typically self-limiting; accounts for 30-60% of sporadic acute hepatitis in India
• Key distinguishing feature: mortality ~20% in pregnant women (unique among hepatitis viruses)
• Does not typically cause chronic liver disease (exception: immunocompromised patients)

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Histopathology / Morphology

Acute Viral Hepatitis

• Liver may be normal, enlarged (inflammation), or shrunken (massive necrosis)
• Microscopically:
  • Portal and lobular lymphocytic infiltrate (lymphocytes + plasma cells + eosinophils)
  • Hepatocyte injury - necrosis or apoptosis (acidophil/Councilman bodies = apoptotic hepatocytes)
  • Ballooning degeneration of hepatocytes (swollen, pale)
  • Confluent necrosis in severe cases; can progress to bridging necrosis (connecting portal tracts/central veins) or panlobular necrosis (= massive hepatic necrosis/acute liver failure)

Chronic Viral Hepatitis

• Inflammatory cells cross the limiting plate → interface hepatitis (periportal hepatocyte injury)
• Fibrosis progression:
  • Portal/periportal fibrosis →
  • Fibrous septa with portoportal bridging fibrosis →
  • Cirrhosis (end stage)

Virus-Specific Histologic Clues:

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Clinicopathologic Syndromes

1. Acute asymptomatic infection - elevated transaminases or antiviral antibodies found incidentally
2. Acute symptomatic infection - incubation → preicteric phase (malaise, nausea, RUQ discomfort) → icteric phase (jaundice) → convalescence
3. Acute liver failure (fulminant hepatitis) - massive hepatic necrosis; viral hepatitis = ~10% of cases; HAV most common worldwide; HBV more common in Asia/Mediterranean
4. Chronic hepatitis - defined as symptomatic, biochemical, or serologic evidence of hepatic disease for >6 months; may progress to cirrhosis and HCC
5. Carrier state - harbor and transmit virus without symptoms (HBV, HCV, HDV)

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Autoimmune Hepatitis

• Chronic, progressive; female predominance (78%)
• Associated with HLA-DR3/DR4 in type 1
• Type 1: ANA + anti-smooth muscle antibody (ASMA, 65%) + anti-SLA/LP (25-35%) - most common form
• Type 2: Anti-LKM-1 + anti-LC1 + anti-SLA/LP - children/teenagers
• Up to 30% of adult-onset cases already have cirrhosis at diagnosis

Morphology of Autoimmune Hepatitis:

• Interface hepatitis or confluent (perivenular/bridging) necrosis
• Plasma cell predominance in the inflammatory infiltrate (distinguishes from viral hepatitis)
• Hepatocyte "rosettes" - circular arrangement of regenerating hepatocytes around dilated canaliculi
• Responds well to immunosuppression (90% remission rate)

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Key Complications

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Hurqatul Baul (حرقة البول) - Burning Micturition / Dysuria

Definition

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Description

Location of Pain

• In men: Pain is typically felt in the distal urethra; it is present only with voiding and disappears soon after micturition is completed
• In women: Pain is usually localized to the urethra or vulva
• Suprapubic pain at the end of voiding suggests bladder inflammation (cystitis)
• Pain at the beginning of urination typically points to urethral pathology
• Pain throughout voiding suggests involvement of both the bladder and urethra

Types of Dysuria

Associated Symptoms

• Frequency - voiding small volumes repeatedly
• Urgency - sudden, strong urge to void
• Hematuria - blood in urine (present in ~50% of UTI cases)
• Suprapubic discomfort
• Vaginal discharge / pruritus - suggests vaginitis rather than UTI
• Fever, chills, flank pain - suggest upper UTI (pyelonephritis) or prostatitis
• Purulent urethral discharge - suggests STI (gonorrhea, chlamydia)

Clinical Significance

• Dysuria significantly increases the probability of UTI
• In women with dysuria + frequency without vaginal discharge, probability of cystitis is >90%
• Dysuria with vaginal discharge or odor lowers the likelihood of UTI and raises suspicion for vaginitis or STI
• Empirical treatment based on dysuria alone leads to unnecessary antibiotic use - other symptoms must be incorporated

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Causes of Hurqatul Baul (Burning Micturition)

I. Infective Causes (Most Common)

A. Lower Urinary Tract Infections (UTI / Cystitis)

• The most common cause overall
• Pathogens: E. coli (~75%), Klebsiella pneumoniae, Proteus mirabilis, Staphylococcus saprophyticus, Enterococcus
• More common in women (short urethra), pregnant women, diabetics, elderly, patients with indwelling catheters
• Presents with internal dysuria + frequency + urgency + suprapubic pain

B. Upper UTI - Pyelonephritis

• Ascending infection reaching the kidney
• Dysuria with fever, chills, flank pain, costovertebral angle tenderness, nausea/vomiting
• Elderly may present atypically with confusion, lethargy

C. Urethritis

• Gonococcal urethritis (Neisseria gonorrhoeae): purulent discharge + dysuria; abrupt onset
• Non-gonococcal urethritis (NGU) (Chlamydia trachomatis, Ureaplasma urealyticum): scant mucoid discharge; may be asymptomatic; gradual onset
• History of new/multiple sexual partners is a key clue
• More common in young, sexually active individuals

D. Vaginitis (in women)

• Bacterial vaginosis (Gardnerella vaginalis): fishy odor, grey discharge
• Candidal vaginitis (Candida albicans): white cottage-cheese discharge, intense pruritus
• Trichomoniasis (Trichomonas vaginalis): frothy, greenish-yellow, malodorous discharge; dysuria + dyspareunia

E. Prostatitis (in men)

• Acute bacterial prostatitis: fever, chills, perineal pain, dysuria, difficulty voiding; exquisitely tender prostate on DRE
• Chronic prostatitis/pelvic pain syndrome: recurrent dysuria, pelvic discomfort

F. Herpes Simplex Virus (HSV)

• Genital HSV (HSV-2 usually) causes painful vesicles/ulcers on genitalia
• Dysuria is severe, particularly external; associated with inguinal lymphadenopathy

G. Other Infections

• Epididymitis/Orchitis (Chlamydia, Gonorrhea in young men; E. coli in older men)
• Tuberculosis of the urinary tract - chronic dysuria, sterile pyuria, frequency
• Schistosomiasis (S. haematobium) - terminal hematuria + dysuria

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II. Non-Infective Inflammatory Causes

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III. Obstructive / Structural Causes

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IV. Neoplastic Causes

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V. Other / Miscellaneous Causes

• Psychogenic / functional dysuria - no organic cause found; associated with anxiety
• Urethral syndrome - predominantly in women; internal dysuria + pyuria with negative culture; caused by subclinical infections or pelvic floor dysfunction
• Radiation proctitis/cystitis - pelvic radiation effects
• Reactive arthritis (Reiter's syndrome) - triad of urethritis + arthritis + conjunctivitis; sterile dysuria
• Behcet's disease - genital ulcers + dysuria
• Atrophic urethritis/vaginitis - post-menopausal women; decreased estrogen → thin mucosa → burning

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Summary of Causes (Quick Reference)

HURQATUL BAUL - CAUSES

INFECTIVE
├── Bacterial UTI (cystitis) ← most common
├── Pyelonephritis
├── Urethritis (gonococcal / non-gonococcal)
├── Vaginitis (bacterial, candidal, trichomonal)
├── Prostatitis (acute / chronic)
├── Herpes genitalis (HSV)
└── Others: TB, Schistosomiasis, Epididymitis

INFLAMMATORY (non-infective)
├── Interstitial cystitis
├── Radiation cystitis
├── Chemical/drug-induced cystitis
└── Vulvitis / atrophic vaginitis

OBSTRUCTIVE / STRUCTURAL
├── Urinary calculi
├── BPH
├── Meatal stenosis / urethral stricture
└── Urethral diverticulum

NEOPLASTIC
├── Bladder carcinoma
├── Prostate carcinoma
└── Vulvovaginal neoplasms

OTHERS
├── Psychogenic
├── Reactive arthritis
└── Behcet's disease

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Diagnostic Approach (Brief)

1. History: onset (sudden vs. gradual), discharge, sexual history, medication use, hygiene products
2. Urinalysis: leukocyte esterase + nitrite dipstick; microscopy (pyuria = ≥10 WBC/mm³)
3. Urine culture: midstream clean-catch specimen
4. STI screen: NAAT for Chlamydia and Gonorrhea if risk factors present
5. Pelvic exam in women: assess for vaginitis, cervicitis
6. Imaging (USG/CT): if stones, obstruction, or pyelonephritis suspected
7. Cystoscopy: if hematuria, recurrent symptoms, or malignancy suspected

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Anthelmintic Drugs - Modern Pharmacology

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Overview

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Drug of Choice by Organism (Katzung Table 53-1)

Nematodes

Trematodes (Flukes)

Cestodes (Tapeworms)

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Individual Drug Profiles

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1. BENZIMIDAZOLES

A. Albendazole

B. Mebendazole

C. Triclabendazole

D. Thiabendazole

• Older benzimidazole; largely replaced by ivermectin/albendazole
• Alternative for strongyloidiasis and cutaneous larva migrans
• Rapidly absorbed; chelating agent (forms complexes with metals, but not calcium)
• Significant adverse effect profile: nausea, vomiting, dizziness, hepatotoxicity - limits use

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2. MACROCYCLIC LACTONES

A. Ivermectin

B. Moxidectin

• Newer macrocyclic lactone; similar mechanism to ivermectin (GluCl channel agonist)
• FDA-approved (2018) for onchocerciasis in patients ≥12 years
• Longer half-life than ivermectin; single-dose efficacy
• Being evaluated for lymphatic filariasis and other nematode infections

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3. PRAZIQUANTEL

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4. DIETHYLCARBAMAZINE (DEC)

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5. PYRANTEL PAMOATE

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6. NICLOSAMIDE

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7. PIPERAZINE

• Mechanism: Flaccid paralysis of worms (GABA receptor agonist → hyperpolarization of muscle)
• Alternative for Ascaris lumbricoides and Enterobius
• Largely replaced by benzimidazoles in current practice
• Antagonistic with pyrantel (opposing mechanisms - do not combine)

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Mechanisms of Action - Summary Table

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Pregnancy Safety

• Avoid throughout pregnancy: Ivermectin, Thiabendazole, Piperazine
• Avoid in first trimester (may use 2nd/3rd in MDA programs): Mebendazole, Albendazole
• Caution: Praziquantel, Triclabendazole (limited data)
• DEC - avoid in pregnancy; associated with adverse fetal effects

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Special Clinical Scenarios

• Neurocysticercosis: Albendazole (preferred) + corticosteroids to reduce inflammatory edema around dying parasites
• Hydatid disease (Echinococcus): Albendazole + surgical/PAIR procedure; must monitor LFTs/CBC
• Hyperinfection strongyloidiasis (in immunocompromised/HTLV-1/steroid users): Ivermectin urgently; mortality up to 90% untreated
• Lymphatic filariasis MDA: Triple therapy - DEC + Ivermectin + Albendazole (superior efficacy)
• Ocular cysticercosis: Praziquantel contraindicated; albendazole with caution; surgical management preferred

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Antiviral Drugs - Modern Pharmacology

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Principle: Sites of Action

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Classification of Antiviral Drugs

ANTIVIRAL DRUGS
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├── ANTI-HERPESVIRUS AGENTS
│   ├── Nucleoside Analogs: Acyclovir, Valacyclovir, Famciclovir, Penciclovir
│   ├── Anti-CMV: Ganciclovir, Valganciclovir, Cidofovir, Foscarnet, Letermovir
│   └── Others: Docosanol, Trifluridine (topical)
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├── ANTI-INFLUENZA AGENTS
│   ├── Neuraminidase Inhibitors: Oseltamivir, Zanamivir, Peramivir
│   ├── Cap-endonuclease Inhibitor: Baloxavir marboxil
│   └── M2 Ion Channel Blockers: Amantadine, Rimantadine (Influenza A only)
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├── ANTI-HIV (ANTIRETROVIRAL) AGENTS
│   ├── NRTIs: Zidovudine, Tenofovir, Emtricitabine, Lamivudine, Abacavir, Stavudine
│   ├── NNRTIs: Efavirenz, Nevirapine, Rilpivirine, Doravirine, Etravirine
│   ├── Protease Inhibitors: Ritonavir, Darunavir, Atazanavir, Lopinavir, Saquinavir
│   ├── INSTIs: Raltegravir, Elvitegravir, Dolutegravir, Bictegravir, Cabotegravir
│   ├── Entry/Fusion Inhibitors: Enfuvirtide, Maraviroc
│   └── Pharmacokinetic Booster: Cobicistat, Ritonavir
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├── ANTI-HBV AGENTS
│   ├── Nucleoside Analogs: Entecavir, Tenofovir, Lamivudine, Adefovir, Telbivudine
│   └── Interferon: Pegylated IFN-α2a/2b
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├── ANTI-HCV (DAA) AGENTS
│   ├── NS5B Polymerase Inhibitors: Sofosbuvir
│   ├── NS5A Inhibitors: Ledipasvir, Velpatasvir, Pibrentasvir
│   └── NS3/4A Protease Inhibitors: Glecaprevir, Grazoprevir, Simeprevir
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├── ANTI-RSV AGENTS
│   └── Palivizumab, Nirsevimab (monoclonal antibodies); Ribavirin
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└── BROAD-SPECTRUM
    └── Ribavirin, Interferons

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I. ANTI-HERPESVIRUS AGENTS

A. Acyclovir

B. Valacyclovir

• L-valine ester prodrug of acyclovir; oral bioavailability 54% (vs 15-30% for acyclovir)
• Converted to acyclovir by intestinal/hepatic valacyclovirase after absorption
• Same mechanism, spectrum, and adverse effects as acyclovir; allows less frequent dosing
• Preferred over acyclovir for most oral HSV/VZV indications

C. Famciclovir / Penciclovir

• Famciclovir = oral prodrug of penciclovir (diacetyl ester); oral bioavailability ~77%
• Mechanism: same as acyclovir (viral TK activation → DNA polymerase inhibition/chain termination)
• Unlike acyclovir, penciclovir-TP does NOT act as obligate chain terminator but has a longer intracellular half-life (10-20 hours)
• Clinical uses: genital HSV, herpes labialis (1500 mg single dose), herpes zoster
• Penciclovir is also available topically for herpes labialis

D. Ganciclovir / Valganciclovir

E. Cidofovir

F. Foscarnet (Phosphonoformate)

G. Letermovir

• Novel anti-CMV drug targeting CMV terminase complex (UL56 subunit) - completely different mechanism from ganciclovir/foscarnet/cidofovir
• Active against ganciclovir-resistant CMV
• Approved for CMV prophylaxis in CMV-seropositive hematopoietic stem cell transplant recipients
• Adverse effects: nausea, diarrhea, edema; CYP3A4 interactions

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II. ANTI-INFLUENZA AGENTS

A. Neuraminidase Inhibitors (first-line)

• Resistance: H275Y mutation in neuraminidase (common in H1N1); use baloxavir as alternative
• Key points: Must begin within 48 hours of symptom onset for maximum benefit; reduce duration of illness by ~1-1.5 days; also reduce complications

B. Baloxavir Marboxil (Xofluza)

• Mechanism: Inhibits cap-dependent endonuclease (PA subunit of viral RNA polymerase complex) → blocks initiation of viral mRNA transcription ("cap snatching") - novel mechanism
• Active against Influenza A and B, including strains resistant to neuraminidase inhibitors
• Single oral dose; prodrug converted to active baloxavir acid
• Adverse effects: diarrhea, headache; should not combine with polyvalent cation-containing products (dairy, antacids) - reduce absorption

C. M2 Ion Channel Blockers (largely obsolete)

• Amantadine, Rimantadine
• Mechanism: Block M2 ion channel of Influenza A → prevent viral uncoating
• Active only against Influenza A (Influenza B lacks M2 protein)
• Nearly 100% resistance among circulating H3N2 and H1N1 strains - no longer recommended for treatment/prophylaxis
• Amantadine also used in Parkinson's disease (dopaminergic effect)
• Adverse effects: CNS (confusion, insomnia, hallucinations - more with amantadine), GI

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III. ANTIRETROVIRAL (HIV) AGENTS

A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

B. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

C. Protease Inhibitors (PIs)

D. Integrase Strand Transfer Inhibitors (INSTIs)

E. Entry/Fusion Inhibitors

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IV. ANTI-HBV AGENTS

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V. ANTI-HCV (DIRECT-ACTING ANTIVIRALS - DAAs)

HCV Targets

Key Regimens (pangenotypic preferred)

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VI. ANTI-RSV AGENTS

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VII. BROAD-SPECTRUM / MISCELLANEOUS

Ribavirin

• Purine nucleoside analog (guanosine analog)
• Mechanisms: (1) Inhibits IMPDH → depletes GTP pool; (2) inhibits viral RNA capping; (3) immunomodulatory (Th1 shift); (4) mutagen (lethal mutagenesis in some viruses)
• Uses: Chronic HCV (historical - with pegylated interferon); inhaled RSV; Lassa fever; hantavirus; ribavirin + valganciclovir for congenital CMV
• Adverse effects: Hemolytic anemia (dose-limiting); teratogenic (absolute contraindication in pregnancy - contraception required during treatment and 6 months after in both partners); rash, cough (inhaled)

Interferons (IFN-α)

• Mechanism: Bind to cell surface receptors → activate JAK-STAT pathway → induce expression of interferon-stimulated genes (ISGs) → antiviral state; also enhance NK cell and T cell activity
• Pegylated IFN-α2a and 2b: PEGylation extends half-life (once weekly dosing)
• Uses (historical): Chronic HBV, chronic HCV (largely replaced by DAAs), hairy cell leukemia, Kaposi sarcoma, condyloma acuminata
• Adverse effects: Flu-like syndrome (universal; fever, chills, myalgia, fatigue); myelosuppression (neutropenia, thrombocytopenia); neuropsychiatric (depression, suicidality); autoimmune disorders; thyroid dysfunction; alopecia; injection site reactions

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Summary: Mechanisms of Action

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