Hepatic Disorders in Children

• Most children with liver problems will have mild symptoms early in the disease, while some may not show any symptoms at all.
• General symptoms of liver disease in children can be mistaken for other mild conditions, such as the flu.
• These general symptoms include:
  • Nausea and vomiting
  • Generalized tiredness or malaise
  • Loss of appetite with dehydration or headache

Hepatomegaly

• The most common specific symptom of liver problems in children is hepatomegaly.
• Enlargement of the liver can be due to several mechanisms.
• It is a mass descending below the right costal margin and costal angle, moves early with respiration, and cannot be palpated above. It has two lobes with a notch between them, and the upper border is at the 5th intercostal space (ICS) in the midclavicular line (MCL).
• In children, the normal liver edge can be felt up to 2 cm below the right costal margin. In a newborn infant, extension of the liver edge >3.5 cm below the costal margin in the right midclavicular line suggests hepatic enlargement.

Jaundice

• Jaundice may be the earliest and only sign of hepatic dysfunction.
• Caused by the deposition of bilirubin in the skin, it is a common manifestation of liver problems.
• Bilirubin is a byproduct of normal cell metabolism and is usually eliminated by the liver. When the liver is damaged, it cannot eliminate bilirubin appropriately, leading to its deposition under the skin and in the conjunctiva (the white part of the eyes).
• Yellow discoloration of the sclera, skin, and mucous membranes is a sign that hyperbilirubinemia exists.
• Clinically apparent jaundice in children and adults occurs when the serum concentration of bilirubin reaches 2-3 mg/dL (34-51 μmol/L); however, a neonate may not appear icteric until the bilirubin level is over 5 mg/dL (85 μmol/L).
• Hyperbilirubinemia can be conjugated or unconjugated.
• An unconjugated hyperbilirubinemia may indicate increased production, hemolysis, reduced hepatic removal, or altered metabolism of bilirubin.
• A conjugated bilirubinemia (>20% of total) reflects decreased excretion by damaged hepatic parenchymal cells or disease of the biliary tract, which may be due to sepsis, endocrine or metabolic disease, inflammation of the liver, or obstruction.

Pruritus (Itching)

Intense itching, often generalized, but sometimes localized to the hands and feet. Pruritus in liver disease is primarily due to the accumulation of bile salts in the skin, which occurs when bile excretion is impaired.

Spider Angiomas

Small, spider-like blood vessels visible on the skin, typically on the face, neck, upper chest, and arms. These are a result of increased estrogen levels due to impaired liver metabolism and are commonly seen in chronic liver disease, particularly cirrhosis.

Palmar Erythema

Reddening of the palms, particularly over the hypothenar and thenar eminences. Palmar erythema is also linked to increased estrogen levels and is commonly seen in chronic liver disease.

Xanthomas

Yellowish deposits of cholesterol in the skin, often seen around the eyes (xanthelasma), on the elbows, knees, or buttocks. Xanthomas occur due to impaired lipid metabolism in liver disease, leading to elevated cholesterol levels.

Portal Hypertension

Increased pressure in the portal vein, leading to complications such as ascites, variceal hemorrhage, and splenomegaly. Portal hypertension is a common consequence of cirrhosis and other chronic liver conditions.

Ascites

Accumulation of fluid in the abdominal cavity, leading to abdominal swelling and discomfort. Ascites is often a result of portal hypertension and reduced albumin production by the liver.

Variceal Hemorrhage

Life-threatening bleeding from dilated veins (varices) in the esophagus or stomach, which develop due to increased pressure from portal hypertension. Variceal hemorrhage is a serious complication of advanced liver disease.

Encephalopathy

A spectrum of neuropsychiatric abnormalities ranging from mild confusion to coma. Hepatic encephalopathy occurs due to the accumulation of toxins (e.g., ammonia) that the liver normally detoxifies, leading to impaired brain function.

• Hepatitis: Inflammation of the liver.
  • Tender hepatomegaly
  • Fever, nausea, vomiting, jaundice, dark urine, fatigue, joint pain
• 50% of children do not develop jaundice.
• Large tender liver is common.
• 30% will have spleenomegaly
• Coagulation is usually normal.
  • Liver function derangement such as high ALT/AST

Viral Hepatitis

• Types:
  • Acute hepatitis
  • Chronic hepatitis:
    • Chronic Persistent Hepatitis – asymptomatic
    • Chronic Active Hepatitis → Cirrhosis of the liver → HCC

• Hepatotropic viruses (A to G) are responsible for 90-99% of viral hepatitis.
• McCallum in 1947 labeled the two known hepatitis viruses A and B.
• Other viral agents include:
  • Yellow Fever
  • Lassa
  • Ebola
  • Herpes
  • Marburg
  • Epstein-Barr
  • Cytomegalovirus
• Seronegative hepatitis

Causes of Acute Hepatitis/ALF

• Infection:
  • Viral:
    • Hepatitis A, B, C, D, E
    • Epstein-Barr virus
    • Cytomegalovirus
    • Yellow fever
  • Bacteria:
    • Leptospirosis
  • Parasite:
    • Toxoplasma gondii
• Toxins:
  • Alcohol
  • Drugs: PCM, Isoniazid, Halothane
  • Amanita phalloides (poisonous mushroom)
• Wilson’s disease
• Autoimmune disease
• Reye’s syndrome

Various Causes of ALF
Cause	Examples	Comment
Drugs and Toxins	Acetaminophen Amanita phalloides Isoniazid Halothane	Acetaminophen poisoning is the overall leading cause of ALF in the US
Viral Infection	Hepatitis A Hepatitis B (+/-D) Hepatitis E Herpes simplex virus	Hepatitis C is a very rare cause of ALF
Vascular problems	Shock Heat stroke Tumor infiltrating the liver	Most often seen after cardiac arrest, major blood loss, or iatrogenic ligation of the major blood vessels feeding the liver
Metabolic/Miscellaneous	Wilson Disease Acute fatty liver of pregnancy Alpha-1 antitrypsin deficiency Autoimmune hepatitis	Family screening is appropriate for many metabolic/genetic causes of ALF
Indeterminate	Unknown	Approximately 15%-20% of adult ALF cases, and up to 50% of ALF in children, cannot be attributed to a specific cause.

Some persons, particularly young children, are asymptomatic. When symptoms are present, they usually occur abruptly and can include the following:

• Fever
• Fatigue
• Loss of appetite
• Nausea
• Vomiting
• Abdominal pain
• Dark urine
• Clay-colored bowel movements
• Joint pain
• Jaundice

Pre-Icteric Period

• In Hepatitis A (HA) and Hepatitis E (HE), the onset is abrupt with fever; but in Hepatitis B (HB) and Hepatitis C (HC), the onset is insidious.
• The initial symptoms include: loss of appetite, nausea, vomiting, lassitude, abdominal pain, and diarrhea.
• By the end of this period, the urine darkens. In a few patients, especially children, fever, headache, and upper respiratory tract symptoms are the main manifestations.
• The duration of this period varies from 1 to 21 days, with an average of 5-7 days.

Icteric Period

• The urine deepens continuously, and jaundice appears on the skin and sclera within 2 weeks.
• Subjective symptoms abate.
• Pruritus may appear about 1 week into this period.
• The liver is palpable in 7% of cases, and the spleen is palpable in 20% of cases.
• The period lasts 2-6 weeks.

Convalescent Period

• The jaundice disappears gradually, and symptoms abate or disappear.
• The liver and spleen retract, and liver function returns to normal.
• The period lasts 2 weeks to 4 months, with an average of 1 month.
• About 10% of Hepatitis B (HB) and 50% of Hepatitis C (HC) cases will become chronic hepatitis.
• Acute Hepatitis D:
  • Co-infection with HBV
  • Super-infection with HBV
• Acute Hepatitis E is similar to acute hepatitis A, but cholestasis is more obvious, and symptoms and signs are more severe.
• If women with pregnancy suffer from HE, it may lead to fulminant hepatitis.
• If HBV super-infects HEV or HCV, it may lead to fulminant hepatitis.

• Viral hepatitis is classified based on the duration of the disease. This may be acute or chronic.
• Acute viral hepatitis - less than 6 months.
• Anicteric hepatitis
• Chronic viral hepatitis - more than six months:
  • Chronic active
  • Chronic persistent
  • Chronic lobular
• Current classification of chronic hepatitis uses the Knodell score (aetiology, necroinflammation (stage), and fibrosis (histological grade)).

Viral Hepatitis
Type of Hepatitis	Mode of Transmission
Hepatitis A	Contaminated food and water.
Hepatitis B	Sexual intercourse. Sharing infected needles.
Hepatitis C	Sexual intercourse. Sharing infected needles.
Hepatitis D	Must have hepatitis B. Found mainly in intravenous drug users.
Hepatitis E	Contaminated water from poor sanitation.

Type of Hepatitis
	A	B	C	D	E
Source of virus	feces	blood/ blood-derived body fluids	blood/ blood-derived body fluids	blood/ blood-derived body fluids	feces
Route of transmission	fecal-oral	percutaneous permucosal	percutaneous permucosal	percutaneous permucosal	fecal-oral
Chronic infection	no	yes	yes	yes	no
Prevention	pre/post-exposure immunization	pre/post-exposure immunization	blood donor screening; risk behavior modification	pre/post-exposure immunization; risk behavior modification	ensure safe drinking water

CHARACTERISTIC	HEPATITIS A	HEPATITIS B	HEPATITIS C	HEPATITIS D	HEPATITIS E
Transmission	Fecal-oral (ingestion of contaminated food and water)	Parenteral (injection of contaminated blood or other body fluids)	Parenteral	Parenteral (host must be coinfected with hepatitis B)	Fecal-oral
Agent	Hepatitis A virus (HAV); single-stranded RNA; no envelope	Hepatitis B virus (HBV); double-stranded DNA; envelope	Hepatitis C virus (HCV); single-stranded RNA; envelope	Hepatitis D virus (HDV); single-stranded RNA; envelope from HBV	Hepatitis E virus (HEV); single-stranded RNA; no envelope
Incubation period	2 to 6 weeks	4 to 26 weeks	2 to 22 weeks	Uncertain	2 to 6 weeks
Manifestations or symptoms	Mostly subclinical; severe cases: fever, headache, malaise, jaundice	Frequently subclinical; similar to HAV, but fever, headache absent, and more likely to progress to severe liver damage	Similar to HBV	Severe liver damage; high mortality rate	Similar to HAV, but pregnant women may have high mortality rate
Chronic liver disease	No	Yes	Yes	Yes	No
Vaccines	Available soon, but immunoglobulins give temporary protection	Genetically engineered	None	HBV vaccine is protective because coinfection required	None

Hepatitis A Virus

• HAV antigen was first identified in feces in 1973.
• It is a picornavirus with a diameter of 27 nm.
• The incubation period is 15-50 days.
• In endemic areas, infection is acquired early in life largely due to its fecal-oral mode of transmission.
• Oro-anal sex can also be a mode of transmission.
• Infection is usually asymptomatic, with clinical infection recognized in only 5% of cases.
• It is a self-limiting infection.
• The virus is not directly cytopathic; liver damage is due to immune-mediated cytotoxicity.
• Over 80% of pre-school children in endemic areas have protective antibodies.
• There is no chronic carrier state.
• An effective vaccine is available.
• It is the most common viral hepatitis.
• Clinical presentations:
  • Asymptomatic
  • Mild illness, recovering within 2-4 weeks (Majority)
  • Prolonged cholestatic hepatitis (self-limiting)
  • Acute fulminant hepatitis
  • No chronic liver disease
• Diagnosis: Confirmed by IgM HAV antibody.
• Treatment: No special treatment; rest.
• Prevention in contacts/travelers:
  • Vaccination (Active immunization)
  • Immunoglobulin

Hepatitis B Virus

• This is the most studied of the hepatotropic viruses because its diagnosis has been made easy by the historic discovery of the Australian antigen, now called HBsAg.
• Hepatitis B Virus (HBV) has a global distribution with about 300 million carriers.
• HBV causes about 2 million deaths annually, with 500,000 from fulminant hepatitis.
• About 2 billion people have markers of the disease worldwide.
• The most effective means of transmission is through blood and blood products.
• Routes of transmission:
  • Humoral transmission (parenteral transmission)
  • Mother to infant transmission (vertical transmission)
  • Sexual contact transmission
  • Insect transmission
• Clinical presentations:
  • Asymptomatic
  • Mild illness, recovering within 2-4 weeks (Majority)
  • Acute hepatitis -> Resolution/Acute fulminant hepatic failure (1-2%)
  • Chronic carriers (5-10%)

HBV disease progression

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HBV disease progression

Serological Diagnosis of HBV

• A battery of serological tests is used for the diagnosis of acute and chronic hepatitis B infection.
• HBsAg - used as a general marker of infection.
• HBsAb - used to document recovery and/or immunity to HBV infection.
• Anti-HBc IgM - marker of acute infection.
• Anti-HBc IgG - indicates past or chronic infection.
• HBeAg - indicates active replication of the virus and therefore infectiveness.
• Anti-HBe - indicates that the virus is no longer replicating. However, the patient can still be positive for HBsAg, which is produced by integrated HBV.

Possible Outcomes of HBV Infection`

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Possible Outcomes of HBV Infection`

Prevention

• Vaccination
  • Highly effective recombinant vaccines are now available.
  • Recommended for health care workers, EPI (Expanded Program on Immunization), and neonates of HBsAg-positive mothers.
• Hepatitis B Immunoglobulin (HBIG)
  • HBIG may be used to protect persons who are exposed to hepatitis B.
  • It is particularly efficacious within 48 hours of the incident.
  • May also be given to neonates at increased risk of contracting hepatitis B, such as those whose mothers are HBsAg and HBeAg positive.
• Other Measures
  • Screening of blood donors.
  • Blood and body fluid precautions.

Chronic HBV Carriers

• These are individuals who harbor the virus for >6 months without any evidence of liver disease.
• They should be monitored closely with serial liver function tests, alpha-fetoprotein, and liver ultrasonography.

Hepatitis C Virus

• Previously known as parenteral NonA-NonB hepatitis virus.
• It is the leading cause of chronic liver disease worldwide.
• About 3% of the world population is chronically infected.
• Chronic infection is a major cause of cirrhosis and hepatocellular carcinoma (HCC) in the developed world.
• Most infections (85%) lead to chronicity.
• Transmission is most effective through serum.
• Sexual transmission is rare because of the usually low level of viraemia.
• Vertical transmission is possible with marked viraemia.
• Transmission:
  • Blood transfusion (e.g., Haemoglobinopathies, Haemophilia).
  • Blood transfusion is now rare due to improved screening.
• Clinical Presentation:
  • Acute infection is mild.
  • 50% develop chronic liver disease, which may later progress to cirrhosis or HCC.

Hepatitis D Virus

• Exclusively found in patients with HBsAg.
• Requires HBV for its replication.
• Occurs in coinfection or superinfection states.
• Superinfection has a worse prognosis.
• Common in drug addicts, haemophiliacs, and institutional patients.
• IgM/IgG anti-HDV and HDV-RNA are used for diagnosis.
• Vaccination for HBV prevents HDV infection.
• HBV treatment also treats HDV infection.

Hepatitis E Virus

• HEV is a common cause of epidemic acute hepatitis in various parts of Southeast and Southern Asia, Burma, and West Africa.
• In 1957, it was the cause of an outbreak of acute hepatitis in New Delhi.
• About 2% of blood donors are seropositive in some Western countries.
• HEV is a 27-34nm single-stranded RNA virus.
• Transmitted like HAV as well as vertically.
• Incubation period is about 2-9 weeks.

Detection of the Markers of Hepatitis Virus

• Serologic Marker of A
  • Anti-HAV IgM: Recent infection
  • Anti-HAV IgG: Past infection
• Sero-immunologic Marker of B
  • HBsAg - Anti-HBs
  • HBcAg - Anti-HBc
  • HBeAg - Anti-Hbe
• Serological Marker of C
  • Anti-HCV IgM
  • Anti-HCV IgG

Treatment

• Isolation
• Rest
• Diet
• Anti-virus therapy (Lamivudine, Interferons)

Prevention

• Control of source of infection
• Cut off the route of transmission
• Protection of susceptible population
  • Active immunity
  • Passive immunity
• Treatment of uncomplicated acute viral hepatitis is supportive:
  • Bed rest, avoidance of alcohol, and normal diet
• Fulminant hepatitis is treated with anti-liver failure regimen.
• Chronic HBV and HCV require both supportive and antiviral therapy.