Download chronic hepatitis in children

CHRONIC HEPATITIS
IN CHILDREN
CLASSIFICATION *
• Viral
• Autoimmune
• Drug induced
• Metabolic
VIRAL *
• Hepatitis B
• Hepatitis C
• Hepatitis D
Clinics *
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No sign or very subtle signs
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Yellow discoloration of the sclera, skin, and mucous membranes hyperbilirubinemia.
Clinically apparent jaundice in children and adults occurs when the serum concentration of
bilirubin reaches 2–3 mg/dL (34–51 μmol/L); however, the neonate may not appear icteric
until the bilirubin level is over 5 mg/dL (85 μmol/L).
Jaundice may be the earliest and only sign of hepatic dysfunction. Liver disease must be
suspected in the infant who may appear only mildly jaundiced, but has dark urine or acholic
(light-colored) stools
Intense generalized itching may occur in patients with cholestasis (conjugated
hyperbilirubinemia
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Enlargement of the liver can be due to several mechanisms in viral—acute and chronic
diseases, specific lipid storage diseases: Gaucher, Niemann-Pick, Wolman disease, 1antitrypsin deficiency, Wilson disease, hypervitaminosis A, neonatal iron storage disease
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Vascular spiders (telangiectasias), characterized by central pulsating arterioles from which
small, wiry venules radiate, may be seen in patients with chronic liver disease, usually most
prominent in the face and chest. These are presumably reflective of altered estrogen
metabolism in the presence of hepatic dysfunction.
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PALMAR ERYTHEMA most noticeable over the thenar and hypothenar eminences and on the
tips of the fingers
Xantomas: deposition of lipid in the dermis and subcutaneous tissue. Brown nodules may
develop first over the extensor surfaces of the extremities; rarely, xanthelasma of the
eyelids develops.
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PORTAL HYPERTENSION.
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ASCITES
VARICEAL HEMORRHAGE
HEPATIC ENCEPHALOPATHY:
ENDOCRINE ABNORMALITIES.
RENAL DYSFUNCTION (functional renal
failure in patients with end-stage liver
disease)
• RECURRENT CHOLANGITIS.
• Nonspecific signs of acute and chronic liver
disease include anorexia, abdominal pain or
distention malnutrition and growth failure,
bleeding, which may be due to altered
synthesis of coagulation factors
Laboratory
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• Acute liver cell injury (parenchymal disease) in viral hepatitis
reflects in marked increases in serum aminotransferase levels
• Cholestasis (obstructive disease) involves regurgitation of bile
components into serum; the serum levels of total and conjugated
bilirubin and serum bile acids are elevated. Elevations in serum
alkaline phosphatase, 5′ nucleotidase (5′ NT), and γ-glutamyl
transpeptidase (GGT) levels are also sensitive indicators of
obstruction or inflammation of the biliary tract.
• Severity : hypoglycemia, hyperammonemia, electrolyte imbalance,
continued hyperbilirubinemia, marked hypoalbuminemia, or
prolonged PT or INR unresponsive to parenteral administration of
vitamin K).
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• An elevation in the conjugated bilirubin
level provides a relatively sensitive index of
hepatocellular disease and hepatic excretory
dysfunction
• Cholesterol levels may is markedly elevated
in patients with cholestasis, whether the
cause is intrahepatic or extrahepatic. On the
other hand, with acute liver disease, such as
hepatitis, serum cholesterol levels may be
depressed
IMAGING *
• Ultrasonography (US) provides information about the size,
composition, and blood flow of the liver. Increased echogenicity is
observed with fatty infiltration, and mass lesions as small as 1–
2 cm may be shown. US has replaced cholangiography in detecting
stones in the gallbladder or biliary tree
• Computed tomography (CT) scanning provides information similar
to that obtained by US but is less suitable for use in patients
younger than 2 yr of age because of the small size of structures,
the paucity of intra-abdominal fat for contrast, and the need for
heavy sedation or general anesthesia. Magnetic resonance
imaging (MRI) is a useful alternative. Magnetic resonance
cholangiography can be of value in differentiating biliary tract
lesions. CT scan or MRI may be more accurate than US in detecting
focal lesions such as tumors, cysts, and abscesses.
• Radionuclide scanning relies on selective uptake of a
radiopharmaceutical agent
Liver biopsy is the undisputed best way to assess liver fibrosis or *
cirrhosis; however, it is an invasive procedure that can cause rare, but
potentially life-threatening complications; less invasive ways to
diagnose liver disease, developing and testing clinical tools, like the
Original European Liver Fibrosis Panel and transient elastography.
HEPATITIS B
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Hepatitis B S Ag > 6 months
Variable biochemical tests
Congenital ( 85% rate) or acquired
Other Markers: DNA PCR, HBe Ag, Anti-HB c ,
Anti- HB e
1-5% of acute attacks become chronic
70 % cirrhosis
HCC carcinoma ( monitor alpha fetoprotein)
HEPATITIS B *
• Hepatitis B vaccine
• Hepatitis immunoglobulin
• Treatment: Interferon or Lamuvidine.
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• HBV is a 42-nm-diameter member of the
Hepadnaviridae family, a
noncytopathogenic, hepatotropic group of
DNA viruses. HBV has a circular, partially
double-stranded DNA genome
• The surface of the virus includes two
particles designated hepatitis B surface
antigen (HBsAg):
• The inner portion of the virion contains
hepatitis B core antigen (HBcAg), the
nucleocapsid that encodes the viral DNA,
and a nonstructural antigen called hepatitis
B e antigen (HBeAg),
• HBeAg serves as a marker of active viral
replication. Replication of HBV occurs
predominantly in the liver but also occurs in
the lymphocytes, spleen, kidney, and
pancreas.
• Chronic hepatitis B remains a major public health problem,
affecting approximately about 350 million people globally. The
number of hepatitis B virus (HBV) infected children has not
been fully documented. The natural history of HBV infection
reflects the dynamic host-virus interactions related to the
condition of the host immune system; hence, the clinical
course of HBV differs between children and adults. The
immaturity of immune system in young children is responsible
for the fact that nearly 90% of HBV infections acquired in
infancy and 40-70% HBV infections before the age of 3 years
result in chronic carrier state of the virus. Therefore a large
population is in need of effective and save treatment of this
disease. Significant advances have been made during the last
decades in the treatment of chronic hepatitis B. The
epidemiological situation of HBV infection, its natural history,
clinical outcome with its serious long-term consequences and
therapeutical approach in children are reviewed in the paper.
HEPATITIS C *
• Congenital 1-10% or acquired
• Anti HCV: maternal persist up to 18
months, takes 6 weeks to show.
• HCV RNA: I U
• 6 genotypes 1-6- geographically variable
and determines the response to therapy
• Peg-Interferon and Ribavirin ( duration
depends on genotype)
• The hepatitis C virus (HCV) is a major public health
problem and a leading cause of chronic liver disease.
In the United States, the Centers for Disease Control and
prevention estimates that there are more than 2.7 million
people with ongoing HCV infection.
• HCV is the leading cause of death from liver disease in the
United States.
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• Liver transplantation
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– This procedure is an effective form of therapy
for patients with decompensated cirrhosis
caused by autoimmune hepatitis. This
procedure also may be used to rescue
patients who present with fulminant hepatic
failure secondary to autoimmune hepatitis.
– The long-term outlook after liver
transplantation is excellent, with 5-year
survival rates reported at 90% or more.
Positive autoantibodies and
hypergammaglobulinemia tend to disappear
within 2 years of transplantation.
HEPATITIS D *
• Co-infection with B
• Outcome similar to B
Autoimmune hepatitis *
• Autoimmune hepatitis is now accepted as a
chronic disease of unknown cause, characterized
by continuing hepatocellular inflammation and
necrosis, which tends to progress to cirrhosis.
Immune serum markers frequently are present,
and the disease often is associated with other
autoimmune diseases.
• Autoimmune hepatitis cannot be explained on the
basis of chronic viral infection, alcohol
consumption, or exposure to hepatotoxic
medications or chemicals.
Autoimmune *
• 2 Types serologically
• ASMA, LKM ( liver kidney microsomes)
• Hypergammaglobuliniemia
• Elevated LFT
• Treatment: Prednisone and Azathioprine.
• High relapse rate
Pathophysiology
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• autoimmune hepatitis is the result of a cell-mediated
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immunologic attack. T
this attack is directed against genetically predisposed
hepatocytes. Aberrant display of human leukocyte
antigen (HLA) class II on the surface of hepatocytes
facilitates the presentation of normal liver cell
membrane constituents to antigen-processing cells.
These activated cells, in turn, stimulate the clonal
expansion of autoantigen-sensitized cytotoxic T
lymphocytes.
cytotoxic T lymphocytes infiltrate liver tissue, release
cytokines, and help to destroy liver cells.
• The reasons for the aberrant HLA display are unclear. It may
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be initiated or triggered by genetic factors, viral infections
(eg, acute hepatitis A or B, Epstein-Barr virus infection),
chemical agents (eg, interferon, melatonin, alpha methyldopa,
oxyphenisatin, nitrofurantoin, tienilic acid). The
asialoglycoprotein receptor and the cytochrome monooxygenase P-450 IID6 are proposed as the triggering
autoantigens.
Some patients appear to be genetically susceptible to
developing autoimmune hepatitis. This condition is associated
with the complement allele C4AQO and with the HLA
haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions
are associated with the development of autoimmune hepatitis
in younger patients. HLA DR3-positive patients are more likely
than other patients to have aggressive disease, which is less
responsive to medical therapy; these patients are younger
than other patients at the time of their initial presentation.
HLA DR4-positive patients are more likely to develop
extrahepatic manifestations of their disease
CLINICS *
– Autoimmune hepatitis may present as acute hepatitis,
chronic hepatitis, or well-established cirrhosis.
– Approximately one third of patients present with
symptoms of acute hepatitis marked by fever, hepatic
tenderness, and jaundice. In some patients, the acute
illness may appear to resolve spontaneously;
however, patients invariably develop signs and
symptoms of chronic liver disease. Other patients
experience rapid progression of the disease to acute
liver failure, as marked by coagulopathy and jaundice.
Ascites and hepatic encephalopathy also may ensue.
– The chronic hepatitis associated with autoimmune *
hepatitis may range in severity from a subclinical
illness without symptoms and with abnormal
results on liver chemistries to a disabling chronic
liver disease. Symptoms and physical examination
findings may stem from the various extrahepatic
diseases associated with autoimmune hepatitis.
Common symptoms include the following:
• Fatigue
• Upper abdominal discomfort
• Mild pruritus
• Anorexia
• Myalgia
• Diarrhea
• Cushingoid features
• Arthralgias
• Skin rashes (including acne)
• Edema
• Hirsutism
• Amenorrhea
• Chest pain from pleuritis
• Weight loss and intense pruritus (unusual)
POZITIVE DIAGNOSIS *
• Evidence for an autoimmune pathogenesis includes the
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following:
Hepatic histopathologic lesions composed predominantly of
cytotoxic T cells and plasma cells
Circulating autoantibodies (ie, nuclear, smooth muscle,
thyroid, liver-kidney microsomal, soluble liver antigen, hepatic
lectin)
Association with hypergammaglobulinemia and the presence
of a rheumatoid factor
Association with other autoimmune diseases
Response to steroid and/or immunosuppressive therapy
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• Antinuclear antibody (ANA), primarily in a
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homogenous pattern
Anti–smooth muscle antibody (ASMA) directed at
actin
Anti–liver-kidney microsomal antibody (anti–LKM1)
Antibodies against soluble liver antigen (anti-SLA)
directed at cytokeratins types 8 and 18
Antibodies to liver-specific asialoglycoprotein
receptor or hepatic lectin
Antimitochondrial antibody (AMA) - AMA is the sine
qua non of primary biliary cirrhosis (PBC) but may
be observed in the so-called overlap syndrome
with autoimmune hepatitis.
Antiphospholipid antibodies
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– Hematologic complications
• Hematologic manifestations of hypersplenism
• Autoimmune hemolytic anemia
• Coombs-positive hemolytic anemia
• Pernicious anemia
• Idiopathic thrombocytopenic purpura
• Eosinophilia
– Gastrointestinal complications
• Inflammatory bowel disease (6%): The presence of ulcerative colitis in patients with autoimmune hepatitis
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should prompt performance of cholangiography to exclude PSC.
Celiac disease: One recent study of 140 pediatric patients with autoimmune hepatitis, autoimmune
cholangitis, and overlap syndrome identified 23 patients with celiac disease. 17
Proliferative glomerulonephritis
Fibrosing alveolitis
Pericarditis and myocarditis
Endocrinologic complications
• Graves disease (6%) and autoimmune thyroiditis (12%)
• Juvenile diabetes mellitus
Rheumatologic complications
• Rheumatoid arthritis and Felty syndrome
• Sjögren syndrome
• Systemic sclerosis
• Mixed connective-tissue disease
• Erythema nodosum
• Leukocytoclastic vasculitis: Patients may present with symptoms of leg ulcers.
Febrile panniculitis
Lichen planus
Uveitis
TREATMENT
• Prednisone only (1,5 -2 mg/kg/d) or
• Prednisone + Azathioprine (1,5 -2 mg/kg/d)
• Initial Regimen
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Prednisone, 2 mg/kg/d (up to 60 mg/d),
for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d
Maintenance Regimen
a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg daily
b. Azathioprine at constant dose if added initially
c. Continue daily prednisone dose with or without azathioprine or switch to
alternate day prednisone dose adjusted to response with or without
azathioprine
End Point
a. Normal liver tests for 1-2 years during treatment
b. No flare during entire interval
c. Liver biopsy examination discloses no inflammation 1,5 -2 mg/kg/d)
Drug Related *
Acetaminophen
Erythromicin
Halothane
Estrogen
Valporic Acid
Anabolic steroids
Isoniazide
Ceftriaxone
Sulfonamides
Cyclophosphamide
Phenytoin
OCP
Methotrexate
Chlorpromazine
Drug Related
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• Dose related: 6 MP, methotrexate and
acetaminophen
• Idiosyncratic: phenytoin, phenobarbital
and carbamezipine
Metabolic *
Wilson Disease
Alpha 1 anti-trypsin deficiency
Tyrosiniemia
Niemann-Pick disease type 2
Glycogen storage Disease IV
Cystic Fibrosis
Galactosemia
Bile Acid Synthetic Abnormalities
Wilson Disease *
• Autosomal recessive defect in Copper
metabolism
• Copper accumulation in vital organs
(hepatic tissue, nervous system) leading
to cirrhosis
• Ceruloplasmin and 24 urine collection for
copper
Alpha 1 Antitrypsin Deficiency *
• Defective production of protein leads to
hepatic accumulation and cirrhosis
• AR
• Variable course
• 2nd cause for liver transplant in children
Galactosemia *
• Defect in Galactose uridyl transferase
• Galactose 1 phosphate accumulation is
toxic
• Dietary elimination
Bile Acid Synthetic Defects
• Disorders result from abnormal synthesis
of bile acids
• Cholestasis in infancy is the main
manifestation
• Ursodeoxycholic acid (Actigall) is used for
the treatment
• Reye syndrome presented most commonly at
approximately 6 yr of age, with most cases in the 4–12yr age range
• Usually quiet, lethargic and sleepy, vomiting,
laboratory evidence of liver dysfunction
II. Deep lethargy, confusion, delirium, combative,
hyperventilation, hyper-reflexic
III. Obtunded, light coma ± seizures, decorticate
rigidity, intact pupillary light reaction
IV. Seizures, deepening coma, decerebrate rigidity,
loss of oculocephalic reflexes, fixed pupils
V. Coma, loss of deep tendon reflexes, respiratory
arrest, fixed dilated pupils, flaccidity/decerebrate
(intermittent); isoelectric electroencephalogram
CIRRHOSIS
• The Metavir scoring system is used to
assess fibrosis. Stage 0 indicates absent
fibrosis, stages 1 and 2 are considered
low-grade fibrosis, stage 3 is considered
high-grade fibrosis, and stage 4 is
cirrhosis.
• Steatosis (fat accumulation in the liver)
Fulminant hepatic
failure
• Fulminant hepatic failure : a clinical syndrome resulting
from massive necrosis of hepatocytes or from severe
functional impairment of hepatocytes in a patient who does
not have a pre-existing liver disease. The disorder usually
evolves over a period of fewer than 8 wk.
• Fulminant hepatic failure is a complication of viral hepatitis
(A, B, D, E, possibly C, and others). An unusually high risk of
fulminant hepatic failure occurs in young people who have
combined infections with the hepatitis B virus (HBV) and
hepatitis D
• The disease occurs sporadically and usually without the
parenteral risk factors of HBV or HCV. Epstein-Barr virus,
herpes simplex virus, adenovirus, enterovirus,
cytomegalovirus, parvovirus B19, and varicella-zoster
infections may produce fulminant hepatitis in children
• Various hepatotoxic drugs and chemicals may also cause
fulminant hepatic failure. Predictable liver injury may occur
after exposure to carbon tetrachloride and Amanita
phalloides mushroom or after acetaminophen overdose
• massive destruction of hepatocytes
may represent both a direct cytotoxic
effect of the virus
• hyperimmune response to the virus
that underlies the massive liver
necrosis
• formation of hepatotoxic metabolites
that bind covalently to
macromolecular cell constituents is
involved in the liver injury produced
by drugs such as acetaminophen and
isoniazid;
CLINICS
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• Progressive jaundice, fetor hepaticus, fever, anorexia,
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vomiting, and abdominal pain are common.
A rapid decrease in liver size without clinical
improvement is an ominous sign.
A hemorrhagic diathesis and ascites may develop.
Patients should be closely observed for hepatic
encephalopathy, which is initially characterized by
minor disturbances of consciousness or motor function.
Irritability, poor feeding, and a change in sleep rhythm
may be the only findings in infants; asterixis may be
demonstrable in older children.
Patients are often somnolent or confused or combative
on arousal and eventually may become responsive only
to painful stimuli. Patients may rapidly progress to
deeper stages of coma
Laboratory Findings *
• Serum direct and indirect bilirubin levels and serum
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aminotransferase activities may be markedly elevated.
However, serum aminotransferase activities do not
correlate well with the severity of the illness and may
actually decrease as a patient deteriorates.
The blood ammonia concentration is usually increased,
but hepatic coma can occur in patients with a normal
blood ammonia level.
Prothrombin time is always prolonged and often does
not improve after parenteral administration of vitamin
K.
Hypoglycemia can occur, particularly in infants.
Hypokalemia, hyponatremia, metabolic acidosis, or
respiratory alkalosis may develop.
Treatment *
• advanced hepatic coma should be
treated in an intensive care unit
where continuous monitoring of vital
functions is possible.
• endotracheal intubation , mechanical
ventilation and supplemental oxygen
• electrolyte and glucose solutions
should be administered intravenously
to maintain urine output, to correct
or prevent hypoglycemia
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• Parenteral supplementation with calcium,
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phosphorus, and magnesium may be
required.
Coagulopathy should be treated with
parenteral administration of vitamin K and
may require fresh frozen plasma;
disseminated intravascular coagulation may
also occur. Plasmapheresis may permit
temporary correction of the bleeding
diathesis without resulting in volume
overload. Continuous hemofiltration is
useful for management of fluid overload and
acute renal failure.
Antacids or H2 receptor blockers or both
should be considered because of the high
risk of gastrointestinal bleeding.
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• Patients should be monitored for infection,
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sepsis, pneumonia, peritonitis, and urinary tract
infections. At least 50% of patients experience
serious infectionș ATB
Cerebral edema is an extremely serious
complication that responds poorly to measures
such as corticosteroid administration and
osmotic diuresis
Gastrointestinal hemorrhage, infection,
constipation, sedatives, electrolyte imbalance,
and hypovolemia may precipitate
encephalopathy and should be identified and
corrected.
Protein intake should be restricted or
eliminated. The gut should be purged with
several enemas. Lactulose should be given every
2–4 hr orally or by nasogastric tube in doses
(10–50 mL) sufficient to cause diarrhea.
Overall mortality exceeds 70%.