L19 - Pathology of hepatitis and cirrhosis Flashcards
Overview of liver function
- Processing of dietary amino acids, carbohydrate and lipids
- Synthesis of serum albumin and coagulation factors (I, II, V, VII, IX, X)
- Detoxification of drugs and chemicals
- Metabolism of bilirubin
- Stores glycogen (for gluconeogenesis to regulate blood glucose level)
Liver unit classification
Can be classified into three types:
1) Classical lobule (Structural)
2) Portal lobule (Functional - bile drainage)
3) Liver acinus (Functional - blood supply)
Liver acinus
- Provides the best correlation between blood perfusion, metabolic activity and liver pathology
- Diamond-shape
- Smallest functional unit of liver
- Two portal areas and two central vein reside on the angles of liver acinus
- Can be devide into zone 1, zone 2, zone 3
- Perfusion, nutrients and metabolism (from greatest to least): zone 1> 2> 3
- pathophysiological events like poisoning, (from most affected to least): zone 1> 2> 3
- Under ischaemic condition, most affected (i.e. most prone to shock): zone 3> 2> 1
Hepatitis definition
A diffuse necroinflammatory disease of the liver
Aetiology of acute hepatitis
1) Infections:
i) Viral infection
- Hepatitis A, B, C, D, E Viruses
- Epstein-Barr virus
- Cytomegalovirus
- Yellow fever virus (South America & Africa)
- Echovirus
- Ebolavirus
- Varicella
ii) Bacterial Infection
- leptospirosis
- Q fever
iii) Parasitic Infection
2) Toxins and Drugs
- e.g. Alcoholism
3) Autoimmune diseases
- e.g. autoimmune hepatitis
4) Metabolic diseases
- e.g. Wilson’s disease
(5) Obeisity ?)
viral hepatitis definition
While it can mean any hepatitis caused by any viruses e.g. cytomegalovirus and Epstein-Barr virus, the term “viral hepatitis” is conventionally restricted to infections with the Hepatitis Viruses A, B, C, D and E.
Acute viral hepatitis general presentaion and prognosis
In general, acute hepatitis due to different hepatitis viruses show the same clinical picture - malaise, anorexia & jaundice:
Clinical Course
1) The disease begins after a variable incubation period.
2) Malaise (i.e. generalized weakness) and anorexia (loss of apetitite) are the earliest symptoms
3) Some patients may recover without becoming jaundiced so the patients may not be aware of the disease. Most patients, however, develop the characteristic symptom of jaundice.
4) The serum transaminases and bilirubin levels are raised.
5) In nearly all patients, the jaundice clears within 3 weeks. The duration of the recovery phase is variable, usually more prolonged in hepatitis B and in hepatitis C.
6) Most patients show complete clinical and biochemical recovery within 3 months after the onset of jaundice.
- Grossly, the liver is swollen and congested
- diffuse parenchymal damage
- swelling of the hepatocytes
- cholestasis
- Kupffer cell hyperplasia
- acidophilic bodies in the liver acini (apoptosis - scattered individual cell death)
- Bridging necrosis or even panacinar necrosis in severe cases
(? - The portal tracts are expanded and infiltrated by mononuclear inflammatory cells)
- concomitant hepatocyte regeneration
This fully developed stage of acute hepatitis with spotty necrosis usually lasts several weeks and is followed by complete resolution without scarring.
In some patients, the disease is more severe with massive liver cell necrosis, which corresponds to the clinical syndrome of fulminant hepatitis. A significant proportion of patients with fulminant hepatitis die of the disease.
HAV virology
- Picornavirus
- RNA
- unenveloped
HAV transmission & epidemiology
Transmission:
- faeco-oral route; spreads by ingestion of contaminated water and foods especially shell fish
- Shed in the stool for 2–3 weeks before and 1 week after the onset of jaundice
- Transmission often seasonal from December to May
- Faecal virus titres falling by the time jaundice appears
- No carrier state
Epidemiology:
- occurs throughout the world and is endemic in countries with substandard hygiene and sanitation.
HAV clinical presentation and prognosis
Clinical presentation:
- 2-6 weeks incubation period
- direct cytopathic effect
- 10% symptomatic in children; 50% symptomatic in adult
- acute onset, no chronic carrier state
Prognosis:
- Type A hepatitis is an acute self-limiting disease
- does not become chronic.
- Mild disease will 99% full recovery
- May lead to protracted hepatitis, cholestatic hepatitis, relapsing hepatitis; these will all recover
- Very rarely fatal, e.g in the case of developing fulminant hepatitis (0.1%)
- No cross infection
HAV lab diagnosis & prevention
Lab diagnosis:
- Serology: Anti-HAV (IgM antibody) appears during the attack and persists
- no virus culture
Prevention
- Passive immunity: normal human immunoglobulin
- Active immunity: HAV vaccine
Hepatitis B virology
- A hepadnavirus
- Causes hepatitis
- 8 genotypes (A to H)
Genome:
- Contains DNA genomes
- Small genome with 3200 nucleotides
- Utilizes limited genome to maximal effect - with overlapping Open Reading Frames (4 ORF that translate to 7 proteins)
- DNA genomes are replicated via an RNA intermediate. In other words, their replication involves reverse transcription
Structure:
(from innermost to outermost)
1) (+)-DNA & (-)-DNA encased
2) capsid
3) Outer envelope membrane
Transmission and epidemiology of HBV
Transmission:
- Parenteral route
- Vertical (mother-baby) transmission in perinatal period
- intimate physical contact esp. sexual
- Blood transfusion/ blood products/ needle contamination/ tattooing
- Carrier state exists
Epidemiology
- extremely common in Hong Kong and Southern China
- Every 5 of 10 ppl have been infected by HBV in Hong Kong (1 in 10 is carrier)
- Its incidence varies greatly in different parts of the world (HBsAg is present in 5 - 20% of apparently healthy persons in Southeast Asia and tropical Africa but in only 0.1 - 0.6% in Western Europe and America)
- Globally 350 million chronic HBV carriers (75% are Chinese)
- High risk groups: family members of HBV carrier, harmophiliacs, chronic liver disease patients
Clinical presentation and prognosis of HBV
Clinical presentation:
- The usual clinical attack of acute hepatitis B tends to be more severe than hepatitis A or C
- Incubation period 2-6 months
- 50% of infected adults are symptomatic
- Infected neonates usually asymptomatic, much higher risk of chronicity (up to 95%)
- Acute or insidious onset
Prognosis:
- 95% will recover from acute HBV hepatitis
- subclinical infection is also frequent especially in infants and children
- A proportion of otherwise normal adult patients will not clear HBV from the serum. They become persistent chronic carriers or develop chronic hepatitis
- up to 25-40% of chronic carriers succumb to HBV related illness
- Chronic hepatitis may lead to cirrhosis,
- Chronic hepatitis may progress to develop hepatocellular carcinoma (HCC) – 80%-90% of HCC associated with HBV in Hong Kong (i.e. HBsAg carriers have a much higher risk of HCC than non-carriers)
- In 0.1 – 1% of cases, fulminant hepatitis occurs
- Cross infection may occur
Lab diagnosis and prevention of HBV
Lab diagnosis:
- Serology: HBsAg positive; HBeAg indicates high infectivity; HBV DNA quantitatively indicates viral replication and activity
Prevention
- Vaccination (Active immunity) – based on genetically engineered analogues of HBsAg, leading to production of Anti-HBs
- Passive immunisation: Hyperimmune Hep B Immune globulin (HBIG)
- All infants in HK are immunised ; All health care workers should be immunised
HCV Virology
- Flaviviridae
- a single-stranded linear RNA virus
- enveloped
HCV transmission & epidemiology
Transmission:
- Parenteral route
- Blood transfusion/ blood products(0.02% of HK blood donors)/ needle contamination/ tattooing
(? Vertical (mother-baby) transmission in perinatal period)
(? intimate physical contact esp. sexual)
- carrier state exist in >90% of patients
Epidemiology:
- 170 million carriers worldwide
- 100,000 cases of hepato-cellular carcinoma annually, worldwide
- Greatest incidence rate in Egypt, due to reuse of injection needles in the past
- Carrier state occurs in >90% of patients
- uncommon in Hong Kong, with
- High risk groups include IV drug users, haemophiliacs, chronic dialysis patients, patients with liver disease
HCV clinical presentation and prognosis
Clinical presentation:
Clinical Presentation:
- Usually asymptomatic, lead to chronic carrier state in >90% of patients
- Long incubation period (7-8 weeks)
- insidious onset
Prognosis:
- very rarely leads to fulminant hepatitis
- About 50% of patients with acute hepatitis C progress to chronic hepatitis, leading to cirrhosis with or without development of hepatocellular carcinoma
- Acute hepatitis C tends to be mild clinically. It is associated with a wide spectrum of disease outcome, similar to the pattern of HBV infection
- Cross infection may occur
HCV Lab diagnosis & prevention
Lab diagnosis:
- Serology: HCV infection is recognised by positive anti-HCV antibodies
- PCR: HCV RNA is detectable early, preceding the appearance of anti- HCV by several weeks; quantitatively represent viral load
- No viral culture
Prevention:
- None
- passive anti-HCV is NOT protective
- No vaccination
HCV Infection Treatment
- Pegylated inferferon + ribavirin: >50% viral clearance, reduce liver fibrosis and reverse cirrhosis
- Virus genotype predicts response to treatment
– Genotypes 2 and 3: 88% response
– Genotypes 1, 4, 5, 6 : 48% response
- Duration (24-48 weeks) of treatment depends on genotype and clinical assessment.
- New antiviral drugs licenced: Protease inhibitors: Telapravir, Bocepravir (need to be used in combination with interferon+ribavirin)
HDV Virology
- Defective/ incomplete RNA virus
Special note:
- under natural conditions replicates only in hosts who are HBs-antigenaemic. This is because HDV requires surface antigen of hepatitis B (HBsAg)
- HDV infection is therefore either an acute HBV/HDV coinfection or a superinfection on chronic HBV infection
HDV Clinical Presentation & Prognosis
- Acute HBV/HDV coinfection may be indistinguishable from hepatitis B, though it is associated with a relatively high rate of fulminant hepatitis.
- HDV can transform mild chronic hepatitis B into severe chronic hepatitis & cirrhosis.
HEV virology
- Calicivirus
- RNA
- Unenveloped
HEV Transmission
Transmission:
- faecal-oral route; has caused massive outbreaks of water-borne hepatitis
- No chronic carrier state
- Convalescent patients will shed HEV for weeks
HEV clinical presentation & prognosis
Clinical Presntation:
- 2-9 weeks incubation period
- Acute onset; no chronic carrier state
Prognosis:
- low risk of chronicity
- Full recovery is expected
- No cross infection
- Low risk of chronicity
- Fulminant hepatitis in 1-2% patients; 10-20% in Pregnant
- It may cause severe disease especially in pregnant women
HEV Lab diagnosis & prevention
Lab diagnosis:
- Serology: rising IgG antibody and IgM antibody against HEV antigen
- No viral culture
Prevention: none
Pathogen of Non- ABCDE viral hepatitis
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
- Varicella
- Yellow Fever
- Echovirus
- Ebola virus
Note: These viruses cause injuries to other organs. The liver is not their main target
Laboratory diagnosis of acute hepatitis
1) Clinical Biochemistry
- Elevated liver enzymes (aspartate aminotransferase
AST, alanine aminotransferase ALT) and bilirubin
2) Virology
– Serologic markers for different hepatitis viruses (viral
antigen or antibody), viral DNA or RNA analysis
3) Hematology
– Coagulation studies in very severe form of hepatitis (e.g. fulminant hepatitis)
4) Histopathology
– Liver biopsy has only limited role in uncomplicated cases of acute hepatitis
Histopathology of acute hepatitis
- 5 forms of necrosis:
1) Acidophil bodies; as a result of apoptosis, apoptotic bodies indicating scattered individual cell death (seen in acute viral hepatitis)
2) Zonal necrosis; as a result of death of hepatocytes involving an acinar zone (usually toxic or haemodynamic causes)
3) Bridging necrosis; necrosis across acinar zones (in sever viral hepatitis)
4) Interface necrosis; necrosis around the portal tract (usually autoimmune hepatitis)
5) Panacinar necrosis; necrosis involving all acinar zones (e.g. toxins or severe viral hepatitis)
[necrotic regions/ necrotic cells stained deeper & more pinkish in H&E]
[Massive & sub-massive necrosis will be observed in severe cases]
- concomitant hepatocyte regeneration
- diffuse parenchymal damage
- swelling of the hepatocytes
- cholestasis
- Kupffer cell hyperplasia
Alcoholic liver diseases
1) Normal liver exposed to alcohol, may develop a reversible condition of steatosis (fatty liver; fatty change, perivenular necrosis). Severe exposure of alcohol to normal liver will also lead to a reversible condition of alcoholic hepatitis (Liver cell necrosis, inflammation, Mallory bodies, fatty change)
2) Severe exposure of alcohol in steatolic stage liver will also lead to alcoholic hepatitis
3) If alcohol abstinence is achieved, steatotic stage and alcoholic hepatitis will be reversed and liver becomes normal.
4) However, continued exposure to alcohol in steatosis will lead to fibrosis, further fatty change, inflammation & scaring. The fibrotic scar tissues will irreversibly replace hepatocyte, leading to cirrhosis
5) Repeated attacks of alcoholic hepatitis will also contribute to repeated extensive fibrosis, and the irreversible cirrholis
Clinical course of HBV infection
Cirrhosis histopathology
- normal acinar structure of the liver is replaced by nodules of regenerative hepatocytes (regenerative nodules) separated from one another by irregular bands of fibrous tissue (fibrous septa)
- diffuse presentation affecting the entire lung
Alcoholic cirrhosis
- Excessive alcohol consumption is associated with several pathological changes in the liver: fatty change, alcoholic hepatitis, hepatic fibrosis, and cirrhosis.
Epidemiology:
- In chronic alcoholics with a daily consumption of > 60 g alcohol in males (or > 20 g in females) for at least 10 years, only about 35% of them develop hepatitis and only 1/3 of these develop cirrhosis. There are wide individual variations.
Pathogenesis:
1) Normal liver exposed to alcohol, may develop a reversible condition of steatosis (fatty liver; fatty change, perivenular necrosis). Severe exposure of alcohol to normal liver will also lead to a reversible condition of alcoholic hepatitis (Liver cell necrosis, inflammation, Mallory bodies, fatty change)
2) Severe exposure of alcohol in steatolic stage liver will also lead to alcoholic hepatitis
3) If alcohol abstinence is achieved, steatotic stage and alcoholic hepatitis will be reversed and liver becomes normal.
4) However, continued exposure to alcohol in steatosis will lead to fibrosis, further fatty change, inflammation & scaring. The fibrotic scar tissues will irreversibly replace hepatocyte, leading to cirrhosis
5) Repeated attacks of alcoholic hepatitis will also contribute to repeated extensive fibrosis, and the irreversible cirrholis (The pathogenesis of alcoholic hepatitis and cirrhosis is not understood)
Cirrhosis & portal hypertension
In the liver, the pressure of the hepatic artery is very high while the pressure in hepatic portal vein is very low. Hepatic portal vein supploed 3/4 of liver blood
Under normal condition, sphincter exists in hepatic arterioles that contract to decrease the pressure of arterial blood before meeting and mixing with the low blood pressure portal vein, so that both bloodstream will be drained into sinusoids
In cirrhosis, however, architectural damage will lead to disruption of these arterial sphincters and create sinusoidal & post-sinusoidal block, due to extensive fibrosis & damage
As a result, blood pressure of arterial blood will not be reduced before meeting with portal vein stream. Moreover, resistannce in sinusoid also increase.
Consequently, blood from the haptic artery may enter hepatic portal vein (which is usually under low pressure & low resistance), leading to portal hypertension
Portal hypertension & varices
- The portal venous bed dilates and the portal-systemic collateral anastomoses enlarge.
- This increase in pressure will lead to varicose vein in the esophagus (esophageal varices), in stomach (gastric varices) around the umbilicus (perumbilical caput medusae) & at the anus (anorectal varices - NOT hemorrhoids)
- The most clinically significant is at the gastro-esophageal junction where esophageal varices occur as bleeding from these esophageal varices is very often torrential and can be fatal.
acidophil/ apoptotic body (usually found in acute viral hepatitis)
- more pinkish and deeper stained
- diffused
Sub-massive/ massive necrosis of hepatocytes (hepatitis)
- (?) possibly zonal necrosis as the more pinkish patches surrounds central vein
Typical Presentation of chronic hepatitis, showing:
portal tract infiltrates of mononuclear inflammatory cells (blue arrow; darkly stained cells)
Classical histology of liver under chronic HBV infection:
- Homogenous ‘ground-glass’ cytoplasm indicates accumulation of HBsAg in these hepatocytes
Autoimmune hepatitis, because:
- Plasma cell-rich infiltrate in the portal tracts
Cirrhosis of the liver
- Diffuse presentation
- regenerative nodules
- fibrosis
Cirrhosis
- Fibrotic septa
- Diffuse replacement by regenerative hepatocytes
Fatty Liver
- fatty change of hepatocytes
- liver enlargement
Esophageal varices
Perumbilical caput medusae
