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1

What is the functional unit of the liver an dhow does this relate to blood flow/hepatitis

Lobule!

Blood enters from the triads, exits from the central vein

Most blood flows into the liver via the portal vein, which collects bloood from the entire GI tract

Remaining blood is oxygenated blood supplied by portal artery (20%)

These vessels continue to bifurcate—> small venues and arterioles ultimately terminating in the sinusoids which are small blood vessels with fenestrated endothelium (ie there are holes) that are lined by hepatocytes

These terminate in the central vein, from which the blood exits. A lobule has a central vein in the center, around which like spokes of a wheel are the portal traits. Each triad has a branch of the portal vein, a branch of the hepatic artery, and a small bile duct (triad)

Blood enters in the triad, flows through the sinusoids to the central vein, then exits the liver

Hepatocellular necrosis around the portal triad, where inflammation occurs not usually infectious because lots of things cause inflammation in the liver

2

What is hepatitis

Hepatic inflammation/injury

Hepatic cell necrosis (cell death)

May be acute or chronic; diverse etiologies;
- bacterial, fungal, parasitic infections
- immune disorders
- metabolic diseases
- lack of perfusion/oxygenation
- toxic injury (medications, toxins, herbals, alcohol)
- viral infections

Inflammation is around the portal triads

Many things can cause hepatitis, most not due to viral infection

3

Viral hepatitis

Numerous viruses can infect the liver

However the term viral hepatitis is reserved for those viruses that target the liver specifically - they are hepatotropic

Hepatitis viruses are lettered sequentially:
- Hepatitis A
- Hepatitis B
- Hepatitis C
- hepatitis D
- hep E
- non A/ nonB - old term used for viral hepatitis of unknown origin

While all hepatitis viruses cause hepatitis, the viruses themselves are quite differnet. The severity of their symptoms can vary in frequency and severity

4

Acute Hepatitis -symptoms

Frequency nad severity varies with virus

Mechanism is the same: immune-mediated damage to infected hepatocytes

Less specific sx—> more specific sx

Fever fatigue malaise nausea vomiting—> abdominal pain—> right upper quadrant abdominal pain—> hepatomegaly—> jaundice (icteric phase) with dark urine, pale stools, puritus (itchy skin), sclera icterus

Fulminant hepatitis- massive hepatic necrosis leading to death a rare outcome
- HEV causes this most commonly, followed by HAV and less frequently by HBV and HCV

NB hep A, B and C all cause an acute illness characterized by nausea, malaise, jaundice. Symptoms dont distinguish these viruses nor do they tell you that the hepatitis is due to a virus infection eg alcoholic cirrhosis is very common

5

Jaundice

Yellow discoloration of the skin, sclera, and mucus membranes

Sclera icterus (white of the eyes are yellow)

Due to systemic retention of pigmented bilirubin in tissues

Puriritus-itchy skin

You need to know about bilirubin because you can measure it - an important lab test

6

Bilirubin - breakdown product of hemoglobin

Conjugated = direct
Unconjugated = indirect
Total bilirubin = direct + indirect

Bilirubin not soluble; binds to albumin aand is transported to the liver

Conjugation occurs in liver, improves solubility

Erythrocytes are destroyed by macrophages in the spleen and bone marrow releasing hemoglobin which is degraded to heme; the globin is metabolized to its constituent amino acids while heme is converted into unconjugated bilirubin in macrophages of the spleen and bone marrow, bound to plasma albumin and transported to the liver

In the liver it is conjugated with glucuronic acid making it water soluble for excretion in the bile

Conjugated is most hepatic causes
Also hemolytic anemia, EHEC, malaria etc

7


Bilirubin metabolism and elimination

Jaundice can result from increased production, decreased excretion or both

Pre hepatic causes (mostly unconjugated bilirubin, indirect)

- increased bilirubin production (hemolytic anemia’s)
- reduced hepatocellular uptake (drugs interferences with transport systems)
- impaired conjugation (diffuse hepatocellular disease, hepatitis)

Post hepatic causes
(Mostly conjugated bilirubin, direct)

Decreased hepatocellular excretion - Dublin Johnson syndrome

Impaired bile flow
- biliary obstruction

More than one mechanism can operate to produce jaundice

Normally unconjugated bilirubin contributes more to the total serum bilirubin than the conjugated form since the later is produced n the liver and secreted into the bile

8

In addition to impaired bilirubin metabolism, death of hepatocytes releases various enzymes

Serum level of these enzymes (called Liver Function Tests) reflects the severity of disease

Follow LFTs over time to monitor disease progress
- ALT (alanine aminotransferase): more specific for liver abnormalities than other enzyme tests, high ALT suggests viral rather than alcohol hepatitis

- AST (aspartate aminotransferase): less specific, since AST present in muscle and other tissues, this is a mitochondrial enzyme also present in heart, muscle, kidney and brain and so is less specific for liver disease, in many cases of liver inflammation the ALT and AST activities are elevated in a 1:1 ratio

- AP (alkaline phosphatase): again less specific, but is indicative of bile cut injury, liver and non liver related disease elevated


- GT (gamma glutamate transpeptidase: often elevated in those who use alcohol or other liver toxic substances to excess

9

Chronic Hepatitis - symptoms

See image of cirrhosis end stage liver slide 13

If acute infection isnt cleared, patient may develop chronic hepatitis

Caused only by hep B and C with variable frequency

Can be
- asymptomatic (chronic p ersistent hepatitis)
- symptomatic (chronic active hepatitis; CAH)

Can lead to bad outcomes:
- cirrhosis (refers to the way the liver scars due to damage)
- hepatocellular carcinoma (malignant cancer, often induced by hepB or C but never A

10

Cirrhosis Liver

13 + 14

Bridging fibrosis in core biopsy
- fibrous bands connecting portal triads

As liver becomes cirrhosis it shrinks in size, externally it appears modular and is quite firm to the touch
- shrunken, micronodular, firm to touch

As it becomes cirrhosis, it becomes more difficult to pump blood through it—> elevated portal pressures

Liver cirrhosis- bridging fibrosis (bands of births scar tissue that connect the portal triads

Major cause of cirrhosis are chronic alcohol abuse, hep C, hep B

11

Cirrhosis

Rigid non compliant liver results in portal hypertension

Resulting symptoms just follow the anatomy —> increased venous pressure throughout leads to fluid transduction (ascites)

Increased pressure in the portal system: things back up - spleen enlarged, pressure in the venous system is increased and as a result fluid leaks out due to hydrostatic pressure giving rise to ASCITES (fluid in abdominal space)

Other outcomes ar hemorrhoids a nd esophageal varies - engorged veins in the lower esophagus, which if torn can lead to massive and life threatening blood loss since there is nothing to stop the bleeding

12

Classic presentation of cirrhosis

Patient who vomits copious amounts of bright red blood (suggests upper GI tract bleed and this is a medical emergency)

13

Cirrhosis also has metabolic consequences

Causes portal hypertension (—> varices, large spleen etc and ascites) and hepatic insufficiency (—> jaundice and hepatic encephalopathy)

Decreased clotting factors: coagulopathy

Decreased glycogen storage: hypoglycemia

Increased ammonia: hepatic encephalopathy (liver is not detoxifying blood insufficiently, you get high ammonia levels)

14

Hepatitis A virus

RNA picornavirus
- small
- RNA positive strand
- single serotype worldwide
- nonenveloped - quite stable outside the body
- acute disease and asymptomatic infection ONLY! No chronicity
- no cytopathic; symptoms result from immune-mediated destruction of virus infected cells, typical acute infection lifestyle

Spread by fecal oral route only and is acid stable; causes acute infections; infection confers life long immunity; there is a vaccine; infection is usuallly symptomatic, usually self-limited. Damage to the liver is from the immune response

15

Hep A virus pathogenesis

Enters bloodstream through oropharynx, replicates in GI tract then viremia spreads to liver

Virus produced and released into bile, and then shed into stool for about 10 days before symptoms appear

HAV replicates slowly in liver and is not cytopathic

Liver pathology due to immune response directed against virus-infected cells

16

Hep A virus: epidemiology

Affects 1.4 million worldwide annually

Common cause of acute haptitis

Enteric transmission
- spread person to person via fecal oral route
- acquired from contaminated food and water
- stable in fresh and salt water for long periods: shellfish common source- contaminated water; as filter feeders they concentrate the virus

Infection confers immunity

HAV outbreaks usually originate from a point source (daycare center, water supply, restaurant)

Spreads readily - infected people are contagious before they are symptomatic

Get HAV vaccine before traveling

17

HAV infection rates have decreased in the US by > 90% in recent years

Due to vaccine1!!

Since children are normally asymptomatic they play an important role in the sprea dof community outbreaks where virus is spread between close contacts

Now most outbreaks are associated with contaminated food

Mechanisms of food borne spread of HAV
1) clean food may be contained by a food handler who is incubating HAV
2) food may be contaminated at its source, eg shellfish harvested from waters contaminated with sewage or crops irrigated with contaminated water

Maternal-fetal Transmission and parenteral Transmission through blood transfusions are NOT major risk factors for HAV transmission (but HBV and HCV are)

18

Recent HAV outbreaks

Frozen strawberries in Virginia

Frozen scallops from the Philippines—> HAV outbreaks in several stages including sushi chain

19

Hep A virus; clinical sx

Acute self-limited- no chronic infection, no association with cancer; > 80% adults symptomatic

Symptoms occur abruptly 15-50 days post exposure, intensify for 4 - 6 days before icteric (jaundice phase)
- incubation is around 1 month and a duration of around 1 month

Infection usually asymptomatic in children

Hepatomegaly in 80%

Jaundice 70% adults, 15% children

Less common = splenomegaly, rash

Fulminant hepatitis rare 1 - 3 per 100

20

Hep A virus Diagnosis

Clinical symptoms/signs, their timing and identification of aknown infected source

Lab findings:
- increase in LFTs/bilirubin

Detect: serum HAV igM
- enzyme immunoassay
- 100% with acute HAV
- remain + for 3 - 6 months

IgG antibodies
- early in convalescence
- prior exposure to HAV (or vaccine)
- remain detectable for decades, 85% of individuals who are infected with HAV have a full clinical and biochemical recovery within 3 months, and all by 6
IgM is gold standard for diagnosing acute infection

21

HAV Treatment/control

Treatment: supportive since HAV is self limited

Full recovery within 3 months most common

Maintenance of sanitary conditions
- handwashing, cooked foods, avoid impure water

HAV vaccine
- two inactivated HAV vaccines available
- indications: travel, chronic liver disease
- recommended for children as routine immunization

22

HBV

Genome covered by the core antigen (HBcAg) which is surrounded by a lipid envelope and the surface Ag (HBsAg)

- HBsAg can assemble into subviral particles, not infectious but more common than virus in the blood of infected people

Another viral protein, called E antigen (HbeAg) is secreted from infected cells and can be detected in patient sera

HBsAg forms the basis of the vaccine that you have received

HBV has a partially dsDNA genome
- makes new DNA from viral RNA by using reverse transcriptase

23

HBV characteristics? Enveloped? Genome?

Dane particle?

HBV enveloped (spared by body fluids) with a partially double stranded DNA genome

Has a rather bizarre replication strategy in that it has a reverse transcriptase (RT) but not an integrase

Some drugs that work against HIV1 RT protein also work against the HBV RT protein, such as lumivudine, an NRTI

Viral DNA covered by core antigen HBcAg which in turn is covered by a lipid membrane from which protrudes the viral surface Ag (HBsAg) which can self assemble to form virus-like particles that can be found in the plasma of infected people—> forms the basis of recombinant subunit HBsAg vaccine

Subviral particles are much more common in the serum of patients that the real virus = DANE PARTICLE

24

HBV: what limits the effectiveness of antibodies

Presence of high levels of subviral particles since Ab bind to subviral particles and are soaked up

25

HBV epidemiology

About 400 million chornically infected worldwide

Between .7 - 1.4 mill chronically infected in US

Parenteral transmission
- IV drug use
- sexual transmission
- health care workers at risk

**major routes of infection are IV drug use and sexual transmission
HBV vaccine has decreased transmission

26

Geographic Distribution of Chronic HBV infection

Why are rates of HBV infection so high?

So high because chronic asymptomatic infections, especially in children

In highly endemic areas, hepB is most commonly spread from mother to child at birth (perinatal Transmission) or through horizontal transmission (exposure to infected blood), especially from an infected child to an uninfected child during the first 5 years of life

Development of chronic infection is very common in infants infected from their mothers or before the age of 5 years

27

HBV in the adult: natural history

Most ppl infected with HBV (75%) will not even know they were infected - they are asymptomatic and the virus is cleared

What makes HBV different from HAV is that sometimes the immune response does not clear infection; these people now become chronically infected, and usually remain so for the rest of their lives

Chronically asymptomatic - may have flare ups but are generally asymptomatic

Changes of progressing from acute to chronic HBV is primarily determined by the agent at infection
- younger you are, the more likely your immune response will be modest - clear infection and asymptomatic

90% perinatal acquired HBV progress to chronic disease, then 29-50% for HBV between age 1 - 5 years, 5 - 10% for adult acquired HBV infections
- chances of sympatomatic infx increase with time

2 bad outcomes of chronic infection are progressive cirrhosis —> liver failure and hepatocellular carcinoma
- coinfection with HIV, hep C virus, and superinfection with hep D virus can lead to accelerated disease progression

28

HBV clinical manifestations

Acute
- 70% subclinical = unlike hep A
- longer incubation period (several months) than hepA
- symptoms improve after 1 - 3 mo

Chronic HBV
- many pt asympatomatic for years
- fatigue most common symptom
- hepatomegaly early in course
- persistence depends on age at infx
- may be detected by observing increased LFTs in an asymptomatic person
- HBV is major cause of hepatocellular carcinoma

29

HBV and hepatocellular carcinoma

- chronic HBV infx increases risk of HCC by > 100 x
- 80% of all HCC attributable to HBV
- HCC one of the three most common causes of cancer mortality in the world
- HBV may induce HCC indirectly by promoting continued liver repair and cell growth in response to tissue damage
- integration and expression of some viral proteins may also promote tumor development directly by juxtaposing viral promoters next to cellular growth controlling genes (HBV can insert into the chromosome)

30

How do you tell if a patient is HBV infected? HBV serologies- what can you measure and what they mean

HBsAg - HBV surface antigen 9part of virus), if positive, patient is acutely or chronically infected

HBeAg - presence of E Ag (another viral protein) is indicative of high levels of infectious virus

Anti-HBsAg IgG - if positive then either vaccinated, infected in the past, or chronically infected if HBsAg also positive

Anti-HBCAg - IgG means that the patient has been infected in the past becuase HBcAg is NOT part of the vaccine; IgM means acute infection

Anti-HBcAg IgM - antigen B core antigen Ig M - detecting IgM that recognizes the core antigen means that the patient is acutely infected with IgM - positive IgM—> acute infection (doesnt predict whether the pt will become chronically infected)