Lecture 9: Infectious Causes of Hepatitis/Drugs & Toxins

Viral Hepatitis

Prodromal (Pre-icteric) Phase: Malaise, Nausea, Vomiting, Fever, RUQ pain

Icteric: Jaundice, dark urine

Very high AST & ALT (usually ≥ 400)

mild-moderate ↑ ALP

unless in liver failure, ↑ serum Bilirubin; Conjugated (Direct) is typically higher

urine + for Bilirubin

Lab values increase early in the prodrome, peak before jaundice is maximal, & fall slowly during the recovery phase

Urinary bilirubin usually precedes jaundice

Acute Hepatic Failure

massive hepatic necrosis; viral Hepatitis causes

caused by HAV + HEV

Carrier state

HBV only: + HBsAg, with no Anti-HBs, & normal Aminotransferases

Hepatitis A

Does NOT lead to chronic infection or carrier state; NOT a risk factor for cancer

Spread: Fecal-oral (close contact, contaminated food or water)

Virus Not cytopathic; Cytotoxic T-cells destroy infected cells

IgM Ab appears at onset of symptoms

IgG confers lifelong immunity

Causes Acute Liver Failure in newly infected (particularly those with other chronic liver disease)

Dx: IgM anti-HAV

vaccine

Hepatitis B Types of Clinical presentations

Clinical presentation determined by host immune response:

Acute Hepatitis followed by recovery & clearance of virus

Acute Hepatic Failure due to massive liver necrosis

Chronic Hepatitis (with or without progression to cirrhosis)

Asymptomatic “healthy” carrier state

Hepatitis B

Transmission: Parenteral; Blood (IV drugs sharing of needles, transfusions), sex, vertical (during childbirth)

HBsAg (surface Ag) → appears before symptoms; peaks in acute, symptomatic period;

HBsAg persistence beyond 6 months indicates chronicity

Anti-HBs (Antibody to HBsAg) → IgG begins to rise generally after disappearance of HBsAg → persists for life; confers immunity; basis of vaccine

In cases that progress to CHRONIC disease, ANTI-HBsAg IS NOT PRODUCED

Chronic disease: Positive HBsAg with Negative Anti-HBsAg

Anti-HBc (Antibody to Core Antigen) → IgM followed by IgG is present in both acute & chronic infections

Present in natural infections; absent in vaccinated

+ HBeAg or HBV quantitative PCR → high viral load/active viral replication

infectious to others (persistence indicates Chronic Hepatitis)

HBeAg-negative Hepatitis B (via mutational loss of e antigen) may also cause Chronic disease

Vaccine produces Anti-HBsAg only! (Anti-HBc is negative)

Chronic Hepatitis B

Persistent ↑ ALT, AST, HBeAg with HBsAg & No Anti-HBsAg

HBeAg, HBV-DNA, & HBV DNA Polymerase signify active viral replication

Some cases of Chronic infection (HBsAg +, Anti-HBsAg -), Transaminases ALT/AST become normal (Carrier state)

Hepatitis B Clinical Manifestations

Acute infection is mild or subclinical in majority

Anorexia, fever, jaundice, RUQ pain

Most cases resolve without treatment

Acute liver failure low

Infection persists & becomes chronic

risk of chronic infection is greatest in infants that acquired it vertically

Immune complex-mediated phenomena (from HBsAg-anti HBs immune complexes)

PAN (Polyarteritis Nodosa) & Glomerulonephritis (Membranous or Membranoproliferative) usually within a year after infection

Chronic infection (particularly if acquired at birth) is a risk factor for developing Hepatocellular Carcinoma

Vaccination is highly effective

Rx for Chronic disease: Interferon & antivirals but complete cure unlikely because HBV can integrate into host DNA

Hepatitis D

Entirely Dependent on HBV for its life cycle (occurs only as coinfection with HBV)

Defective RNA virus that can only produce infection in Hepatitis B infected hepatocytes because HDV requires encapsulation by HBsAg

Transmission: Parenteral

Virus only produces one protein, HDAg

Coinfection of healthy patient (HBV + HDV at same time): usually self-limited acute hepatitis with clearance of both viruses

Superinfection (chronic HBV carrier gets exposed): Higher risk of fulminant acute hepatitis & progression to cirrhosis & HCC

Dx: Total Anti-HD antibodies. Confirm with measurement of HDV RNA in serum.

Hepatitis C

Chronic Hepatitis

Transmission: Parenteral

Fluctuating elevations of Transaminases

Few individuals clear the virus

Many develop Cirrhosis over 20 to 30 years & have ↑ risk of HCC

Detectable HCV RNA in blood

Screen with anti-HCV (false negative very early in infection or in immunosuppressed)

HCV-RNA viral load test

Rx: specific & highly effective antiviral drugs available (virus does not integrate into host DNA; true cures possible)

Hepatitis C Complications

Cryoglobulinemia: Monoclonal or Polyclonal IgM cryoglobulins with Rheumatoid factor activity (bind FC of IgG) & Raynaud’s syndrome

Membranoproliferative Glomerulonephritis

Vasculitis (cutaneous, leukocytoclastic)

Porphyria Cutanea Tarda due to Uroporphyrinogen Decarboxylase in the liver; blistering skin lesions that develop on sun-exposed skin (Photosensitivity)

Hepatitis E

Zoonotic disease with animal reservoirs; waterborne & fecal-oral transmitted

Most self-limited

Fulminant Acute hepatitis (liver failure) occurs in infected pregnant women

Chronic disease does not occur in the immunocompetent

No ↑cancer risk

Serology or PCR for viral RNA

IgM anti-HEV at onset of symptoms & rising transaminases

IgG anti-HEV persists

Morphology of Viral Hepatitis

Variable portal & lobular lymphoid infiltrates present

Acute: Apoptotic (with Acidophil bodies) or Necrotic (→ Acute Liver Failure)

Chronic: dense Portal Lymphocytic inflammation with “interface” activity (inflammation extends beyond the limiting plate of the Triads into the liver parenchyma)

Also called “piecemeal necrosis”

Fibrosis (portal → periportal → bridging → cirrhosis) develops

Acute hepatitis

Acidophil body (Apoptosis)

Chronic Hepatitis

portal lymphocytic inflammation with interface activity

Chronic Hepatitis

Bridging fibrosis or Cirrhosis

Hepatitis B: “Ground glass hepatocytes”

Hepatitis B: “Ground glass hepatocytes”

IHC staining for HBsAg

Hepatitis C: Steatosis

Both HBV & HCV: Portal track Lymphoid infiltration with interface activity

Recovery from Acute Hepatitis following necrosis

Recovery may be complete if Reticulin support network is not injured

Postnecrotic Cirrhosis if Reticulin is destroyed

May be due to causes other than viral, such as drugs, chemicals, mushrooms (Amanita phalloides)

Irregular sized nodules (Macronodular Cirrhosis)

Wide fibrous (collagenous) septae

Loss of hepatocytes

Regenerative nodules

Risk for Hepatocellular Carcinoma

Liver Abscesses

Due to mostly to pyogenic bacteria

via Portal vein seeding from appendicitis, diverticulitis, other contaminated abdominal surgeries

via Arterial dissemination (IV drugs, infective endocarditis)

by Ascending the biliary tract (Ascending Cholangitis)

via Direct extension from peritonitis of via Penetrating injury

Fever, RUQ pain, tender Hepatomegaly

Neutrophilia

↑ inflammatory biomarkers (CRP, ESR, Procalcitonin)

↑ ALP; var. ↑ AST/ALT, +/- Jaundice w/ biliary obstruction (↑ Direct Bili)

Frequent in elderly; symptoms less developed; Dx delayed

Large abscess: surgical drainage

Small abscesses: antibiotics

Mortality for large abscesses

Other causes of liver abscesses

hepatic infections are mostly due to Parasites:

Malaria

Schistosomiasis (Intrahepatic “Pipestem Fibrosis”)

Strongyloidiasis

Cryptosporidiosis

Leishmaniasis

Echinococcosis (Hydatid Cysts + calcified walls caused by the larva of small tapeworm)

Rx is surgical resection of the cyst. Liver Bx is contraindicated as accidental entry of cyst fluid into circulation → anaphylaxis

Amebiasis (Dx by serology)

Liver Flukes (live in lumen of bile ducts)

Autoimmune Hepatitis

Chronic Progressive Hepatitis with autoantibodies that responds to immunosuppression

Genetic predisposition; associated with other autoimmune disease; Female

Specific antibody to Liver unknown

Overlaps with other chronic hepatitis

Inflammation of Triads with interface activity; numerous Plasma cells are typical

Lymphs & plasma cells may be seen inside hepatocyte cytoplasm (Emperipolesis)

May see areas of necrosis; usually see fibrosis; may present with Cirrhosis

Autoantibodies, ↑ Serum IgG, liver Bx, Exclusion of other causes

Hepatitis with prominent plasma cells

“Typical for AIH”: Lymphoplasmacytic Portal infiltrate with Interface activity ("piecemeal necrosis")

Microvesicular Steatosis

Reye syndrome usually seen in children & teenagers with use of Aspirin (Salicylates) after viral infections with Varicella or Influenza

Can occur due to a metabolic fatty acid oxidation disorder

Aspirin metabolites inhibit Mitochondrial Beta-oxidation of Fatty Acids (primary path of FA breakdown)

Risk for Acute Hepatic Failure (without necrosis)

Aspirin use is Contraindicated if < 19 years of age (except for Kawasaki Disease)

Poor Px

Fatalities usually due to Encephalopathy

Cholestatic

Bland hepatocellular cholestasis w/o inflammation

Contraceptives/Estrogen; Anabolic steroids, Amoxicillin-Clavulinate, HART

Hepatocellular necrosis

Massive necrosis → Acetominophen; halothane

Chronic hepatitis → Isoniazid (for TB)

Fibrosis and cirrhosis

Periportal and pericellular

Alcohol; methotrexate; enalopril; vitamin A (retinoids)

Granuloma formation

Noncaseating epithelioid granulomas: Sulfonamides; amiodarone; Isoniazid

Fibrin ring granulomas: Allopurinol

Fatty liver

Large and small droplets: ETOH, corticosteroids, methotrexate, total parenteral nutrition

Microvesicular: Valproate; Tetracycline; ASA-Reye syndrome; ART

Steatohepatitis with Mallory-Denk bodies: EtOH; Amiodarone

Vascular lesions

Sinusoidal obstruction/veno-occlusion of central vein

High dose chemotherapy

Bush teas

Budd-Chiari

hepatic vein occlusion

Oral contraceptives

Hepatocellular Adenoma

Oral contraceptives; anabolic steroids

Hepatocellular Carcinoma

ETOH; thorotrast

Cholangiocarcinoma

Thorotrast

Angiosarcoma

Thorotrast, vinyl chloride; arsenic

Alcoholic Liver disease

3 types: steatosis (fatty change), alcoholic steato-hepatitis, fibrosis (→ Cirrhosis)

Excessive alcohol intake causes steatosis, dysfunction of mitochondria, microtubules, cellular membranes, & oxidative stress, → inflammation & hepatocyte death

Mediators of cell injury include Acetaldehyde (induces lipid peroxidation & binds to proteins to form adducts), ↑ CYP2E1 Enzyme (creates free radicals), & ↓ Glutathione antioxidant levels

Alcohol catabolism by Alcohol Dehydrogenase & Acetaldehyde Dehydrogenase consume NAD+ to generate reduced

nicotinamide adenine dinucleotide (↑NADH + H+)

↓ NAD+ results in hepatic steatosis via ↓ fatty acid oxidation

Alcoholic Hepatic Steatosis

lipid accumulation coalesces into large droplets that distend hepatocyte & displace the nucleus (Macrovesicular Steatosis)

Liver is enlarged, yellow, greasy

Alcoholic Hepatitis

Hepatocyte swelling (Balloon cells) & necrosis in background of Steatosis

Mallory-Denk bodies: eosinophilic inclusions formed of damaged cytokeratins which are ubiquitinated

Neutrophilic infiltrate in lobules; variable mononuclear cells

Liver normal to increased size

May progress to alcohol related steatofibrosis → eventual Cirrhosis

Numerous Mallory-Denk bodies

Composed of damaged aggregates of Keratins 8 & 18 which are Ubiquitinated

Alcoholic hepatitis with clustered inflammatory cells marking the site of a necrotic hepatocyte (arrowhead) & Mallory body (arrow)

Alcoholic Steatohepatitis with early fibrosis

Steatohepatitis is often accompanied by perivenular & pericellular (Zone 3) fibrosis with a “chicken-wire” appearance

With continued injury can progress to periportal & bridging fibrosis & then to Cirrhosis

Alcoholic Cirrhosis is usually Micronodular (Laennec Cirrhosis)

Cirrhosis is rarely reversible

Alcohol-related Cirrhosis

Mostly Irreversible fibrosis; evolves slowly

End-stage: brown, shrunken < 1 kg

Nodular “hobnail” gross

Micronodules of trapped regenerative

hepatocytes surrounded by fibrous tissue

Microscopic (end-stage) may be indistinguishable from other causes of cirrhosis

Alcoholic Cirrhosis

Alcoholic Cirrhosis

Alcoholic Liver disease Clinical features

Steatosis: Hepatomegaly, mild ↑ Bilirubin (mostly unconjugated), ALP & GGT; mild increases in Aminotransferases; Reversible Steatohepatitis: tends to appear acutely, after bout of heavy drinking: malaise, anorexia, upper abdominal discomfort, RUQ tenderness

↑ Bilirubin, ALP, & Aminotransferases; often neutrophilic leukocytosis

Serum AST:ALT ratio >2:1

With repeated bouts → Cirrhosis

With cessation, some may clear, but in others, hepatitis persists, & progress to Cirrhosis

May be clinically silent (Compensated) or progress to liver failure (Decompensated)

Portal Hypertension with ascites, esophageal varices; Hyperestrogenism

Liver failure (↓ Albumin, ↑PTT)

Nonalcoholic Fatty Liver Disease spectrum

Hepatic Steatosis (NAFLD): Steatosis in individuals who do not consume alcohol plus, two of: High BP, Dyslipidemia (↑ TG, LDL, or ↓ HDL), central obesity, Microalbuminuria

Associated with Obesity, Type 2 diabetes, Hyperlipidemia (metabolic syndrome)

Nonalcoholic Steatohepatitis (NASH) refers to those of NAFLD that develop Steatohepatitis

NASH ↑risk of developing Cirrhosis

NASH complications- decompensated cirrhosis, hepatocellular carcinoma

In the cirrhotic stage, the Fat may be lost (“burned out NASH”)

Most Isolated Fatty Liver

Nonalcoholic Fatty Liver Disease

Insulin resistance ↑ release of Free Fatty acids from somatic adipocytes

Results in increased FFA uptake in liver, stored as TG

↑ serum ALT/AST

Dx of NASH is by Liver Bx + Clinical history to exclude Alcohol

Fatigue or RUQ discomfort (caused by hepatomegaly)

NASH +/- advanced fibrosis/Cirrhosis

↑ risk of Hepatocellular Carcinoma

Nonalcoholic Steatohepatitis

Fat droplets- small/medium/large; balloon cells; inflammatory infiltrates

Nonalcoholic Steatohepatitis

Perisinusoidal fibrosis – chicken wire most prominent around central vein

Nonalcoholic Steatohepatitis

Perisinusoidal fibrosis – chicken wire most prominent around central vein