HEPATITIS AND CIRRHOSIS

SAMIR EL ANSARY

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Hepatitis is defined as inflammation of

the liver.

It can be divided into

infectious and noninfectious causes.

Liver function tests

The term liver function tests (LFTs)

commonly refers to

Alkaline amino-transferase (ALT),

Aspartate aminotransferase (AST),

Alkaline phosphatase

Bilirubin, albumin, and protein.

Liver function tests

ALT and AST (transaminases) are

enzymes found in hepatocytes

whereas alkaline phosphatase is found in

cells in the bile ducts.

Gamma-glutamyl

transpeptidaseis an additional test that is used to

determine whether

Alkaline phosphatase elevations originate

from hepatobiliary sources.

Prothrombin time is used to

assess liver synthetic

function.

Elevations of which LFTs are associated

with hepatitis

Hepatitis is a process of hepatocellular

inflammation and damage that causes

spillage of cellular elements into the blood.

Hepatitis therefore results primarily in

elevations in ALT and AST.

Elevations can be modest in some forms

of hepatitis (alcoholic) or extreme in

others (acute viral hepatitis).

Alkaline phosphataseLevels can also be elevated in hepatitis,

but elevations are generally less

significant than those of the

transaminases.

BilirubinCan reach very high levels in hepatitis

but usually lags behind the

transaminases.

Types of infectious hepatitis

Hepatitis viruses primarily infect the

liver and include hepatitis

A, B, C, D, and E.

Other nonhepatitis viruses

can cause hepatitis including

Cytomegalovirus, Epstein-Barr

virus, and human

immunodeficiency virus (HIV).

Hepatitis A, how is it diagnosed,

and what are the disease course

and management?Hepatitis A is a disease caused by an RNA virus

that is transmitted by the fecal-oral route, is

endemic in the developing world, and occurs

sporadically in the United States.

Most childhood infections are

asymptomatic.

Adults are more likely to have acute

symptoms.

The incubation period is 2 to 6 weeks, after which

patients have fatigue, malaise, fever, and

abdominal pain followed by jaundice.

Transaminase levels are markedly elevated.

Diagnosis is by a positive anti-hepatitis A

virus (HAV) immunoglobulin (lg) Mantibody that denotes active infection

and remains elevated for 3 to 6 months.

HAV anti-lgG antibody positivity occurs later,

remains elevated for decades, and indicates

past infection.

Treatment is supportive. Significant morbidity and mortality are

uncommon, but development of fulminant

hepatic failure (FHF) can occur (<I%) and

carries significant mortality .

HAV vaccine is effective and widely

available.

It is recommended for individuals with

chronic liver disease, child-care workers,

and those traveling to endemic areas.

Hepatitis E

Like HAV, hepatitis E virus (HEV) is an

RNA virus that is transmitted by the fecal-

oral route.

It is endemic to Southeast Asia, Africa, India,

and Central America.

Infection in the United States is uncommon

and is almost always associated with

individuals who have recently traveled to

endemic areas.

It causes a self-limiting hepatitis similar to

HAV infection but has a significantly higher

tendency to progress to FHF in pregnant

women.

Laboratory tests for diagnosis include HEV

IgG and IgM antibody testing

As well as HEV RNA polymerase chain

reaction (PCR).

Hepatitis B

Hepatitis B is a disease caused by

A DNA virusthat is transmitted through blood and body

fluids.

Risk factors include intravenous (IV) and

intranasal drug use, unprotected sex with

multiple partners, men who have sex with

men, health care workers exposed to blood,

children born to infected mothers,

incarceration, and spouses of infected

individuals.

Acute infection

Is most commonly asymptomatic but

can cause constitutional symptoms

including fatigue, malaise, nausea,

vomiting, headache, arthralgias,

myalgias, and low-grade fever, as well

as jaundice, dark urine, clay-colored

stools, and tender hepatomegaly.

FHF occurs in 1% of infections.

Other complications include a serum

sickness-like syndrome (5%-10% of

cases), glomerular nephritis with

nephrotic syndrome, systemic

vasculitis

And progression to chronic

hepatitis B infection

which occurs in approximately 5% of

cases.

Some individuals go on to a carrier

state in which they have persistent

hepatitis B virus (HBV) in the liver

without any significant

inflammation.

These individuals can be

infectious and are termed

Inactive carriers.

How is hepatitis B

diagnosed

Serologic testing for hepatitis B

is complicated by the fact that

there are multiple blood tests

routinely used to assess

infection.

Hepatitis B surface antigen (HBsAg)Is the lipid and protein layer that forms the outer

shell of HBV.

It is not infectious and is produced in excess

during viral replication. It is the first viral antigen to become positive in the

serum with acute infection, and its presence

indicates active infection.

It may be negative early in the acute infection

And it is also the first serum marker to be cleared by the

host immune system

Becoming undetectable 6 to 12 weeks after infection.

Hepatitis B surface antibody

(HBsAb)

Is the antibody to HBsAg.

It develops to detectible levels 6 to 8 weeks after

infection and remains detectible for life.

Positive HBsAb indicates past or resolving

infection.

Hepatitis B vaccine uses the surface

particle, and vaccinated individuals will also

be HBsAb positive.

Hepatitis B core antibody (HBcAb) is an

antibody to a core viral protein.

HBcAb can be measured as IgG or lgM and can

also be reported as total, which includes both.

lgM makes up the immune system's early

response and is later replaced by IgG.

Positive HBcAb lgM indicates early or acute

infection.

Positive HBcAb IgG indicates past or chronic

infection.

Hepatitis B early antigen (HBeAg)Is a protein produced during viral

replication

And detectible levels of this antigen indicate

high levels of viral replication

Increased infectivity

And higher risk of progression to fibrosis.

It is positive during both acute

infection and active viral phases

of chronic infection.

HBV DNACan also be measured and is one of the

diagnostic criteria

For

Chronic HBV infection.

Hepatitis C

Hepatitis C is caused by a blood-

borne RNA virus. It is transmitted primarily through contact with

blood products from infected individuals.

Risk factors include current or past IV drug use,

health care workers exposed to blood

Or transfusion of infected blood

products(rare since routine screening was introduced in

1992).

Sexual transmission can occur

but is uncommon with hepatitis C

virus (HCV).

Most acute infections are

asymptomatic

But 20% to 30% of infected

individuals will have

A self-limiting illness similar to

other acute viral hepatitis

infections.

A majority (70%-85%) of those

infected with HCV will go on to have

chronic infection.

It is currently estimated that more

than 3 million individuals have

chronic HCV in the United States,

where it is the leading indication for

liver transplantation.

•How is HCV infection diagnosed?

Screening for infection is by serum

testing for anti-HCV antibody.

Antibody positivity occurs at 4 to 10

weeks and remains positive for life

regardless of whether

Chronic infection develops.

All positive antibody tests should be

followed up with an

HCV RNA PCRto determine whether active infection exists.

Of those infected, 15% to 25% will

spontaneously clear the virus and are not at

risk for complications of chronic infection.

If virus is detected

Viral genotyping should be done.

HCV genotypes

And how do they affect

management?

At least six genotypes and more than 50

subtypes of HCV have been identified.

Genotype 1 is the most common genotype,

accounting for 60% to 80% of all hepatitis C.

Genotype 1 is more difficult to eradicate

with treatment than other common

genotypes.

Treatment for chronic hepatitis C

infection is with pegylated

interferon-a and ribavirin.

Treatment length is dependent on genotype

and viral response.

Genotype 1 traditionally requires a longer

treatment course (48 weeks) and has lower

response rates (50%).

Recent data have shown that the

addition of

Telaprevir or Boceprevir to

interferon and ribavirinfor treatment of genotype 1 hepatitis

C infection significantly improves

achievement of sustained viral

response to levels similar to those of

other common hepatitis C

genotypes.

Other extrahepatic conditions

can be caused by

Hepatitis C infection

Some individuals with chronic hepatitis C

infection can have other medical conditions that

are thought to be due to the body's immune

response to the HCV infection.

These conditions are uncommon

They include diabetes mellitus,

glomerulonephritis, mixed cryoglobulinemia,

porphyria cutanea tarda, and non-Hodgkin

lymphoma.

Hepatitis D

Hepatitis D virus (HDV) or hepatitis delta virus

is a small RNA viral particle that can cause

infection only

in the presence of hepatitis B virus.

It is blood borne, and IV drug use is the most

common route of infection. Infection can occur

either as coinfection when both HBV and HDV

viruses are acquired together or as

superinfection when HDV infection occurs in a

patient with chronic hepatitis B infection.

Hepatitis D

Concomitant infection with hepatitis

B and D results in a higher

likelihood of development of FHF

More rapid progression to cirrhosis,

and higher rates of hepatocellular

carcinoma.

Viral serologies should be tested

in a patient with acute hepatitis

All patients with

Acute hepatitis should undergo

testing for

Anti-HAV IgM, anti-HCV antibody,

HBsAg, and HBcAb.

•Who should be screened for HCV

infection?

Because chronic hepatitis C infection is

prevalent and treatment can reduce the

morbidity and mortality associated with

infection, screening is recommended for anyone

who has used injection drugs, people who

received clotting factors before 1987 or other

blood products before 1992, patients

undergoing hemodialysis, those with

unexplained abnormal LFTs, health care

Workers with needle-stick

injuries, individuals positive for

HIV, and babies born to

women positive for HCV.

Patients with similar risk

factors should be screened for

HBV as well.

Risks associated with chronic

hepatitis

Chronic hepatitis can develop with HBV, HCV, and

HDV infections, as well as many nonviral causes

of hepatitis.

It is characterized by persistent liver inflammation.

Chronic hepatitis is

associated with the development of liver fibrosis

and cirrhosis and with increased risk for the

development of hepatocellular carcinoma.

Nonviral causes of hepatitisThere are many nonviral causes of hepatitis,

which can be broken down into several

broad categories including

Toxic or drug induced,

autoimmune, and metabolic.

The list of drugs and toxinsthat can cause liver injury is extensive.

The two most common causes of drug- or

toxin induced liver injury are

Alcohol and acetaminophen.

Nonviral causes of hepatitis

Metabolic causes of hepatitis include

hemochromatosis, Wilson disease, and

nonalcoholic fatty liver disease.

Hepatitis can also develop as a result of

other organ system dysfunction.

An example of this is liver hypoperfusion in

shock states, known as

Shock liver.

Autoimmune hepatitis (AIH)

AIH is a chronic inflammatory liver disease

caused by a host immune response to

portions of the hepatocyte.

This chronic inflammation can lead to

progressive fibrosis and cirrhosis if left

untreated.

AIH can occur at any age but occurs most

often in young women and is commonly

associated with other autoimmune disorders.

Circulating autoantibodies associated

with AIH are antinuclear antibody, anti-

smooth muscle antibody, and liver kidney

microsomal antibody.

Elevated immunoglobulin levels are also

common.

Liver biopsy is necessary for diagnosis of

AlH.

Treatment is with steroids alone or in

combination with azathioprine, and

remission can be achieved in 60% to 80% of

cases.

How is alcoholic hepatitis

managed

Alcoholic hepatitis can have a 1-month

mortality rate as high as 30% to 50%.

The Maddrey discriminant function score

is a validated mechanism to score disease

severity.

It uses Prothrombin time and

total bilirubinTo calculate a disease severity score with

scores >32 indicating severe disease.

How is alcoholic hepatitis

managed

Data suggest that patients with severe

disease benefit from treatment with a 4-week

course of steroids or pentoxifylline if

steroids are contraindicated.

Additionally all patients with alcoholic

hepatitis should be counseled to abstain from

alcohol and should undergo nutritional

assessment and

Receive aggressive nutritional therapy.

FULMINANT HEPATIC FAILURE

{FHF}

FHF or acute liver failure is a gastrointestinal

emergency characterized by the rapid arrest of

normal hepatic function.

A defining feature of FHF is the rapid onset of

hepatic encephalopathy.

FHF can result from the most severe forms of

most of the causes of hepatitis.

This includes the viral hepatitides, drugs,

toxins, autoimmune hepatitis, and metabolic

conditions affecting the liver.

In addition to encephalopathy, FHF

can result in coagulopathy,

increased risk for infection,

metabolic derangements

including acute renal failure,

electrolyte abnormalities,

hypoglycemia

And pancreatitis.

Significant cardiorespiratory and

hemodynamic sequelae of FHF

also occur that are characterized

by

Hypotension resulting from low

systemic vascular resistance,

increased cardiac output, and

tissue hypoxia.

Treatment and prognosis of FHF

Treatment for patients with FHF is supportive

while allowing the liver time to regenerate.

Mortality rates are high, and the only

intervention with proved benefit is

Liver transplantation.

Early referral to a transplant center should be

considered when FHF is suspected.

Some causes of FHF can be

reversed with immediate treatment

and should be assessed for rapidly.

These include acetaminophen,

amanita mushroom poisoning, herpes

simplex virus, acute fatty liver

disease of pregnancy, and Wilson

disease.

•What is cirrhosis?

Cirrhosis is a progressive process of

hepatic injury, subsequent fibrosis, and

destruction of normal liver architecture.

It may result from any chronic liver

disease but is most commonly

associated with viral hepatitis and

alcoholic liver disease.

What are the causes of cirrhosis?

The most common causes of cirrhosis are

Alcoholic liver disease and hepatitis C.

Cryptogenic cirrhosis accounts for up to

18% of cases.

Many cryptogenic cases may be due to

nonalcoholic

fatty liver disease.

Other causes include hepatitis

B, autoimmune hepatobiliary

disease, hemochromatosis,

extra-hepatic biliary

obstruction, Wilson disease

a,-antitrypsin deficiency

and drug toxicity.

Clinical presentation of cirrhosis

Cirrhosis is often asymptomatic

and discovered incidentally.

Well-compensated

cirrhosisCan manifest as anorexia and

weight loss

weakness, and fatigue.

More progressive diseasemay present with the following signs:

jaundice, pruritus, coagulopathy, increasing

abdominal girth, splenomegaly, abdominal wall

vascular collaterals (caput medusae), spider

telangiectasia,

palmar erythema, mental status changes, and

asterixis.

Advanced cirrhosis may present with

severe complications such as upper

gastrointestinal tract bleeding or hepatic

encephalopathy.

How is cirrhosis diagnosed?Liver biopsy provides the definitive

diagnosis of cirrhosis and may be indicated

when the clinical diagnosis is uncertain.

Abdominal ultrasound findings of liver

nodularity, irregularity, increased

echogenicity, and atrophy are consistent with

cirrhosis.

LFTs (including prothrombin time and

albumin), hepatitis serologies,

autoantibodies, and a complete blood cell

count may reveal the underlying causes of

cirrhosis and the extent of liver dysfunction.

Major complications of cirrhosis

The most common complication of

cirrhosis is ascites, followed by

gastroesophageal variceal

hemorrhage and hepatic

encephalopathy.

Ascites and variceal hemorrhage

are direct consequences of portal

hypertension.

Portal hypertension

Portal hypertension is defined as a portal

pressure of

Greater than 12 mm Hgor a hepatic venous wedge pressure that

exceeds the pressure of

The inferior vena cava by

> 5 mm Hg

The portal hypertension of cirrhosis

is caused by

The disruption of hepatic

sinusoids

leading to increased resistance

in the portal venous system.

A compounding effect is increased

portal flow due to vasodilation and

increased cardiac output

associated with cirrhosis.

This leads to an imbalance of

Starling forces, which results in

fluid accumulation in the peritoneal

cavity (ascites), as well as

gastroesophageal varices.

Other complications of

cirrhosis

Altered hemodynamics,

hyponatremia

immune compromise

and

Coagulopathy.

How is cirrhotic ascites

diagnosed?

New-onset ascites should be

assessed with

Diagnostic paracentesis

to confirm cirrhosis as the cause

and rule out

Spontaneous bacterial peritonitis

(SBP).

The Serum/ascites albumin

gradient (SAAG)is the most important diagnostic parameter in

determining the cause of ascites.

A SAAG of > 1.1 g/dL indicates

ascites from portal hypertension

with a specificity of 97%. Ascitic fluid cell count, differential, and total

protein should also be performed.

Ascitic fluid culture should be obtained if any

suspicion of SBP exists.

How is cirrhotic ascites

managed?

Initial management focuses on dietary

sodium restriction and abstinence from

alcohol in alcohol related liver disease.

Diuretic therapy is the mainstay of medical

management of ascites.

Dual therapy with furosemide and

spironolactone is the recommended starting

regimen if renal function is stable.

Large-volume paracentesis is used to

relieve the discomfort of tense ascites.

Serial paracentesis may be indicated

for ascites refractory to medical therapy.

Transjugular intrahepatic portosystemic

shunt (TIPS) and liver transplantation

should be considered in refractory

cases.

Surgically placed peritoneovenous

shunts may be an option in patients who

are not candidates for paracentesis,

TIPS, or transplantation.

Large-volume paracentesis

is used to relieve the discomfort of tense

ascites.

Serial paracentesis

May be indicated for ascites refractory to

medical therapy.

Transjugular intrahepatic portosystemic

shunt (TIPS)

and liver transplantationshould be considered in refractory cases.

TIPSTIPS is a treatment for portal

hypertension.

It is reserved for patients with severe

Ascites and variceal bleeding

who do not respond to medical therapy.

Reduced portal pressure is achieved by

a stent placed through the liver between

the portal and hepatic

circulation.

Complications of cirrhotic ascitesAscites is associated with the

complications of

SPONTANEOUS BACTERIAL

PERITONITIS {SBP}

And the

Hepatorenal syndrome (HRS).

Mortality of cirrhotic ascitesCirrhotic ascites carries a 3-year

mortality rate of 50%.

How is SBP diagnosed and

managed?

A positive ascitic fluid culture and

absolute polymorphonuclear leukocyte

(PMN) count of > 250 cells/mm3

Are diagnostic of SBP in the absence of

an intraabdominal, surgically treatable

source of infection.

Empirical antibiotics should be

initiated for SBP in any hospitalized

patient with an ascetic fluid PMN

count of >250 cells/mm3

or an ascitic protein level of less than

1 g/dL or

in a patient with clinical suspicion

of SBP

(i.e., fever, abdominal pain)

regardless of PMN count.

A third generation cephalosporin

is the initial antibiotic choice, ideally

Cefotaxime. Oral ofloxacin

is an acceptable substitute in patients

who are quinolone naive and are

clinically stable.

Risk factors for SBP, and how is

it prevented

Risk factors for SBP include prior SBP,

variceal hemorrhage, and low-protein

ascites.

Prevention of SBP may be achieved with

use of

Quinolones or a third-generation

cephalosporin in patients with

variceal hemorrhage.

Oral quinolones may be used in

patients who have had prior episodes of

SBP.

Antibiotic prophylaxismay be considered in those

with

low-protein ascites.

HEPATO RENAL SYNDROME

HRS

and how is it managed

HRS is renal dysfunction

(creatinine level >1.5 mg/Dl)

that persists after 2 days of diuretic

withdrawal and volume expansion

in patients with cirrhosis and ascites.

Type I HRS is rapidly progressive and fatal

without treatment.

Type II HRS progresses over months with a

median survival of 3 to 6 months.

Type I HRS warrants an

expedited referral for liver transplantation.

Dialysis may be needed to bridge patients to

transplantation.

Medical therapies such as

Octreotide and Midodrinemay be used as temporizing measures as

well.

Variceal bleeding

Variceal bleeding is upper gastrointestinal

tract bleeding due to rupture of

gastroesophageal varices.

It is the most common life-threatening

complication of cirrhosis and occurs at a

rate of 5% to 15% per year in patients

with cirrhosis.

Size of varices and severity of liver

disease are the most important

predictors of bleeding.

How is variceal bleeding

prevented?

At the time cirrhosis is diagnosed,

esophago-gastroduodenoscopy (EGD)

should be performed to screen for

varices.

If medium to large varices are present

with a high risk of bleeding

Nonselective p-blocker therapy or

Endoscopic variceal ligation (EVL)

is recommended.

For medium varices or small

varices with a high risk of

bleeding

Non-selective p-blocker therapy

is preferred with

Endoscopic variceal ligation

EVL reserved for patients

intolerant to p-blocker therapy.

Other sources of upper

gastrointestinal tract bleeding

in patients with cirrhosis

Sources include portal

hypertensive gastropathy and

gastric antral vascular

ectasia.

•How is variceal bleeding

managed?Acute management consists of volume

resuscitation, blood transfusion to

maintain a hemoglobin level of > 8

g/Dl

and EGD within 12 hours to diagnose

variceal bleeding and treat with

Endoscopic variceal ligation

EVL

or sclerotherapy.

Medications that promote

Splanchnic vasoconstrictionare also used

(Octreotide, a somatostatin

analog

And terlipressin).

Balloon tamponade

Is an effective short-term strategy to

control bleeding, but it carries a 20%

mortality rate due to complications.

TIPS.

Short-term antibiotic treatment

Is indicated in patients with

Variceal bleeding and ascites

Because of their high risk for

SBP, other infections, and subsequent

risk of rebleeding.

A 7-day course ofNorfloxacin

(400 mg twice daily) is recommended.

IV ciprofloxacinMay be used in patients unable to tolerate the

oral route.

CeftriaxoneIs an alternative in areas with high quinolone

resistance.

Hepatic encephalopathy

Hepatic encephalopathy is a

syndrome of altered mental status in

the setting of

Portosystemic shuntingEither through

Collateral vessels or through

surgically placed shunts.

Hepatic encephalopathyThe mechanism is uncertain but may relate to

changes in the blood-brain barrier that allow

passage of neurotoxic substances, including

ammonia and manganese, into the

brain.

Another theory suggests that accumulation of

circulating ammonia due to

Decreased hepatocyte function leads to

encephalopathy.

•How is hepatic

encephalopathy diagnosed and

managed?Elevated serum ammonia levels indicate

hepatic encephalopathy in patients with

cirrhosis and altered mental status that

cannot be explained by any other cause.

Precipitating factors include

gastrointestinal bleeding, infection,

constipation, and metabolic

disturbances.

Treatment focuses on

Reducing intestinal production of

ammonia

Typically through the use of cathartics

(such as lactulose) and antibiotics

(such as neomycin and rifaximin).

Low-protein diets are no longer

recommended as they do not appear to

be effective at reducing

encephalopathy and may contribute to

malnutrition.

The pulmonary syndromes

associated with chronic liver

disease.

Hepatopulmonary syndrome

Is a mismatch of ventilation and

perfusion that results primarily

from :

Vasodilation of pulmonary capillaries.

Arteriovenous communication in the lungs

and pleura may occur as well.

It is characterized by hypoxia and

dyspnea that worsen with upright

position

(orthodeoxia and platypnea,

respectively).

Portopulmonary

hypertension

Is the development of

Pulmonary hypertension

in the presence of

Portal hypertension.

•When should patients with

cirrhosis be referred for liver

transplantation?Patients with cirrhosis should be referred

for transplantation when they have their

first major complication

(ascites, variceal bleeding, hepatic

encephalopathy)

or evidence of significant

Hepatic dysfunction

Hepatopulmonary syndrome is a

mismatch of ventilation and perfusion that

results primarily from vasodilation of

pulmonary capillaries.

Arteriovenous communication in the

lungs and pleura may occur as well. It is

characterized by hypoxia and dyspnea

that worsen with upright position

(orthodeoxia and platypnea,

respectively).

Portopulmonary hypertension is the

development of pulmonary

hypertension in the presence of portal

hypertension.

•When should patients with cirrhosis

be referred for liver transplantation?

Global Critical Carehttps://www.facebook.com/groups/1451610115129555/#!/groups/145161011512

9555/ Wellcome in our new group ..... Dr.SAMIR EL ANSARY

GOOD LUCK

SAMIR EL ANSARYICU PROFESSOR

AIN SHAMSCAIRO

elansarysamir@yahoo.com