Transcript Hepatitis Viruses
Hepatitis Viruses
Dr. Alvaro Barboza Quintana.
Profesor de Patología.
Fac. Medicina UANL.
Escuela de Medicina ITESM .
Causes of hepatitis
Hepatitis can be caused by some viruses, bacteria, parasites, fungi and chemicals as part of the clinical features that characterizes each disease. But the hepatitis viruses, a heterogeneous group of viruses with an special affinity for the liver, are the mayor cause of viral hepatitis.
Liver is often affected by: – Citomegalovirus.
– Mononucleosis.
– Yellow fever.
Virus with high affinity for liver: – Hepatitis virus A.
– Hepatitis virus B.
– Hepatitis virus C.
– Hepatitis virus D.
– Hepatitis virus E.
– Hepatitis virus F.
– Hepatitis virus G.
agent hepatitis HAV HBV icosahe dral capsid, RNA enveloped of acute DNA transmission fecal-oral parenteral; close contact incubation period 2-6 wk 4-26 wk chronic none 5-10% HCV HDV HEV HGV enveloped RNA parenteral; close contact enveloped parenteral; coinfection, RN close contact unenve loped RNA water-borne RNA virus parenteral 2-26 wk 4-7 wk 2-8 wk unknown none >50% <5% 80%superinfect.
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Hepatitis A (HAV)
A benign, self limited disease, known as infectious hepatitis. Accounts for about 25% of clinically evident acute hepatitis.
Epidemiology
Transmission Fecal-oral route. Excreted in the stool of patients 2-3 weeks before, and 8-10 days after, the onset of jaundice. The virus particle is resistant to degradation, remaining infectious in the environment for weeks.
Person-to-person transmission.- cause outbreaks in places like institutions.
Fecal contamination of a single source.- can lead to sudden epidemies.
Hepatitis A virus
Distribution and incidence .
Worldwide infection, especially in areas with substandar hygiene and sanitation.
Clinical disease
HAV causes an acute, highly contagious form of hepatitis:
Clinical infection The pre-icteric stage is characterized by nonspecific, flu-like symptoms of anorexia, nausea, vomiting, and malaise.
The icteric stage is characterized by hyperbilirubinemia, jaundice, hepatomegaly, right upper quadrant tenderness, and raised serum levels of liver enzymes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Morphologic features in acute hepatitis:
Morfologic changes in acute viral hepatitis are shared among hepatotropic virus inflammatory infiltrate, bile duct reaction, balloning degeneration (were the hepatocite cytoplasm looks empty), macrophage aggregates, cholestasis and apoptosis.
Portal tract inflammation, Kupffer's cell hypertrophy and spotty acidophilic necrosis of hepatocytes.
Diagnosis
Clinical data
Serologic tests that detect antibodies to HAV. The finding of IgM anti-HAV antibodies indicates current or recent infection, while the finding of IgG anti HAV antibodies (without IgM antibodies) indicates past exposure to the virus.
Treatment
Supportive therapy. Immunity after HAV infection is usually lifelong, infrequently waning in the elderly. Relapses occur, but chronic carriers of HAV have not been detected. In developing countries, with inadequate sanitation, infection occurs more in childhood. Prevention with killed virus vaccine.
Hepatitis B virus (HBV)
Epidemiology
300,000 people are afected (USA) Endemic in Italy, Grece, Africa and the southeast of Asia The hepatocellular carcinoma endemic in those countries is Asymptomatic patients may have the virus in blood and other body fluids this is why it ’ s easily transmited Incubation period: 6 weeks-6 months
Transmission
Blood Sexual contact Perinatal
Risk group
Drug users that share needles Sexually active people (especially those who are promiscuous) Patients that have dialysis Infants born to infected mothers Healthcare workers
Clinical manifestations
Acute Subclinical infections – Are more common than clinical infections – Liver enzymes are elevated – The severity of the disease is related to the viral dose Jaundice Fatigue Abdominal pain Anorexia Nausea Vomiting
Clinical manifestations
Chronic Carriers: individuals who have detectable HBsAg (hepatitis B superficial antigen) for at least 6 months Of patients that become chronic carriers, the majority (90%) develop chronic persistent hepatitis and rest will develop chronic active hepatitis
Serologic markers for hepatitis B
Serologic markers in chronic HBV
Persistent hepatitis B
They remain clinically well, but they are able to infect other people The liver enzymes may be slightly elevated It can lead to terminal liver failure
Chronic active hepatitis
Patients are more likely to be symptomatic and to have a more severe manifestations
Complications of chronic hepatitis
It ’ s associated with cirrohosis and hepatocellular carcinoma
Limitant plate damage or interface necrosis.
Liver architecture is usually well preserved With lymphoid aggregates in portal tract.
Cirrhosis
Chronic carriers especially those with chronic active hepatitis, may develop cirrhosis
HBV as oncogenic factor
Causes between 250,000-1,000,000 deaths worldwide in a year Approximately 80% of the cases of HC are owed to HBV The period between the infection with HB until the development of HC could be from 9-35 years
Hepatocellular carcinoma. Such liver cancers arise of cirrhosis
Hepatocellular carcinoma.
There is no discernable normal lobular architecture, though vascular structures are present
Prevention
Hepatitis B vaccine (available since 1982) – Routine vaccination of 0-18 year olds Screening pregnant women and treatment of infants born to infected women Screening of blood/organ/tissue donors
Hepatitis C
90% of the cases are associated to transfusions Transmission Blood Needles Sexual intercourse
Hepatitis C virus
Epidemiology
5-10% of the cases are post transfusions It produces cronic hepatitis – Cirrosis in 20% of the cases – Hepatocellular carcinoma the cases in 50% of
Clinical manifestations
It has 2 types: – Acute: It could last 4/6 months Similar to manifestations seen in hepatitis A or B, but with less inflamation – Chronic: More then 10 years Leads frecuently to hepatocelluar carcinoma and cirrosis
Hepatitis C.
Diagnosis and treatment
ELISA Interferon alfa
Hepatitis D virus. Delta agent.
HDV is a defective RNA virus. Needs to be encapsulated by HBsAg.
Superinfection of a chronic carrier of HBV Progression to cirrhosis in 80%
Hepatitis E virus.
High mortality range among pregnant women 20%
Drug and toxin Induced liver Disease
hepatotoxicity from chemicals
Drug Induced liver Disease
Liver is the mayor detoxifying organ in the body.
Liver is subjet to potential damage from pharamceutical and environmental chemicals.
Injury may result from: – Direct toxicity – Hepatic conversion of chemical.
– Immune mechanisms.
Drug Induced liver Disease
Liver damage from chemicals may be immediate or take months.
Forms of liver injury: – Hepatocyte necrosis – Cholestasis – Insidious onset of dysfunction.
– Drug induced chronic hepatitis is indistinguishable from chrinc viral hepatitis
Drug Induced liver Disease
Hepatocelular damage Chemicals
Microvesicular fatty change Tetracycline, salicylates.
Macrovesicular fatty change Ethanol, methrotexate.
Massive necrosis Acetaminophen, insoniazid.
Hepatitis, acute and chronic Methyldopa, phenytoin.
Cholestasis Anabolic steroids, oral contraceptives.
Drug Induced liver Disease
Reye syndrome – Mitochonrdial dysfuntion in liver and some other organs.
– Predminantly in children given acetylsalicylic acid cause of fever.
– Produces microvesicular steatosis with severe liver dysfuntion.
Alcholic liver disease (Ethanol Metabolism)
Epidemiology
It develop only after a "threshold" dose 600 kg for men and 150 to 300 kg for women. one must consume eight 12-oz beers, 1 L of wine, daily for a period of 20 years Almost all people who exceed this threshold dose of ethanol exhibit some biochemical or histologic abnormality suggestive of liver injury
Epidemiology
fewer than 50% of people who ingest the calculated threshold dose of ethanol eventually develop serious alcoholic liver disease (e.g., alcoholic hepatitis or fibrosis).
This suggest that the pathogenesis involves hereditary and enviromental disorders.
Metabolism
Liver. 3 enzyme systems: ADH, MEOS and catalase. There exist several isoforms of the ADH enzyme (alfa, beta and gamma) and variation in this changes the metabolic rate of ethanol. Asians (beta2) 20% faster. ADH acts alone when tissue levels do not exceed 10 mmol/L
MEOS
Cytochrome P-450 2E1 (CYP2E1) also the metabolism of other drugs such as acetaminophen, haloalkanes, and nitrosamines Chronic ethanol consumption up-regulates CYP2E1 CYP2E1-mediated ethanol oxidation yields reactive oxygen intermediates These are capable of provoking hepatocellular damage
Acetaldehyde is a highly reactive and potentially toxic compound. It is metabolized by the ALDH . Half of Chinese people are deficient of this enzyme.
Gastric metabolism
Gastric ADH is implicated in first-pass metabolism of ethanol This limit the ethanol delivery to the portal circulation This enzyme is lower in Women.
Oxidant Stress
DNA is sensitive to oxidant stress. Mitochondrial DNA is more susceptible than nuclear DNA to oxidative damage because of reduced protection by histone and nonhistone proteins and because of a decreased capacity for repair This causes deletion and mutations in DNA
Oxidant Stress
Chronic alcohol consumption indeed leads to depletion of several antioxidants in the liver
Vitamin A depletion causes lysosomal damage
Vitamin E depletion enhaces lipid peroxidation
Glutation depletion impairs mitochondrial function.
Alcoholic liver disease Traditional spectrum of injury * Fatty change * Alcoholic hepatitis * Alcoholic cirrhosis
Alcoholic hepatitis Hepatocyte necrosis Infiltrate of neutrophil polymorphs +/- fatty change +/- Mallory bodies +/- bile stasis
MECHANISMS OF TISSUE DAMAGE 2 ways of damage: Indirect Ingestion of Ethanol Increases the release of endotoxins, from the gram negative bacteria in the natural flora of the intestinal tract Kupffer cells release toxic mediators:Reactive Oxygen Intermediates (ROIs) and Tumor Necrosis Factor (TNF) Synergize to cause oxidative damage to hepatocytes. the inflammatory response.
Direct Damage
Alcohol metabolism consumption deficiency.
Relative NADH NADH NADH deficiency fat metabolism in liver.
Slow / incomplete Accumulation of fat
Injury on structures of the liver
A. Mitochondria
Know as “megamitochondria” 25% of the patient with AAH.
Characterized by: Oxidative fosforilation and Krebs Cycle inhibited (40%) Reduction of the B-oxidation of the fatty acids leading to a “microvesicular esteatosis”
B. citokines.
Elevated plasma levels of: Il,1,6,8, and TNF-alpha.
(the last 2 related to worst prognosis) (seen in 75% of the patients)
C. Kupfer Cells
Secretes high levels of: TNF-alpha. This is a strong factor for adherence and activation of the leucocytes.
IL-8- main mediator for neutrophils atraction
D. Alterations of the hepatocelular protein
Aldehide and ethanol change conformation of the surface proteins. In such way the immune system recognizes them as “Neoantigens”
E. Fibrosis Irreversible Occurs at only 10 – 15% of the alcoholics Due to activation of the Ito Cells (Fat store cells or perisinusoids cells) that are at Disse Spece.
Function: normally stores vitamyn A, But en presence of Ethanol miofibrobñastic cells and Hipersecretes collagen fibrosis
F. Hipoxia
Hipermetabolic state induces aumented O2 usage, leaving the pericentral zone lackting O2. This is because the flow is from the periportal zone to the pericentral zone.
Though it leads to damage of the pericentral zone.
Other cause of perocentral hipoxia is that CYP2E1 is most abundant at the pericentral zone. (main site of metabolism)
Other factors contributing to the lipid accumulation are:
The oversupply of free fatty acids to the liver.
Interference with the triglyceride cycle.
The increased synthesis or esterification of fatty acids Decreased fatty acid oxidation.
Decreased apoprotein synthesis.
Decreased synthesis or secretion of very low density lipoproteins.
This liver is slightly enlarged and has a pale yellow appearance, seen both on the capsule and cut surface. This uniform change is consistent with fatty metamorphosis (fatty change).
Massive hepatomegaly in an elderly alcoholic; the liver weighed 2010 grams. Note the tinge of yellow.
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Micro
ballooning degeneration of hepatocytes, inflammation with neutrophils near mallory bodies Mallory bodies (abnormal perinuclear aggregations of cellular intermediate filament proteins “citokeratin”).
Mallory's hyaline is seen here, but there are also neutrophils, necrosis of hepatocytes, collagen deposition, and fatty change. These findings are typical for acute alcoholic hepatitis. Such inflammation can occur in a person with a history of alcoholism who goes on a drinking "binge" and consumes large quantities of alcohol over a short time.
Mallory´s bodies are positive For CK immunoperoxidase .
Hyaline Mallory´s Bodies In globoid hepatocyte. There Is an interstitial infiltrate of Neutrophils.
Clinical manifestations
Vomiting Diarrhea Jaundice Psychological disturbances.
Hepatic encephalopathy Ascites Bleeding esophageal Varices (varicose veins in the esophagus), abnormal blood clotting and coma.
Main Reason for consulting: Pathologically, it results in an enlarged liver Painful to palpation.
Enlargement is due to the accumulation of fat and the swelling of liver cells, and to the accumulation of proteins that are normally secreted.
Lab
AST to ALT ratio = 2:1 Alkaline Phosphatase elevated Gamma glutamyl transferase (GGT) Hypoalbuminemia
Management
Alcohol Cessation Increased caloric and protein intake Vitamin supplementation (Thiamine) Corticosteroids
Prognosis
Mortality 10-15% from acute hepatitis Cirrhosis develops in 50% of alcoholic hepatitis Alcoholic liver disease Immediate causes of death: * massive gastrointestinal * variceal haemorrhage * hepatic coma * infection * hepatorenal syndrome