This is a 14 year old Caucasian patient who comes to your office with a chief complaint of nausea, poor appetite, and fever for one week. Her fever has been between 101 and 102 degrees, and occurs every day. She had two non-bloody, non-bilious episodes of emesis in the last two days and also has abdominal pain on her right side below the ribs, which has been getting worse. Her urine color is darker than normal, although she has not been drinking much fluid. She denies any coughing, URI symptoms, diarrhea, and dysuria. She is not sexually active and denies drug or alcohol use. She is not taking any medications other than ibuprofen for her fever.
Exam: T38.4, P85, R16, BP 100/70. She has a 2.3 kg (5 pound) weight loss since her last visit 6 months ago. She appears tired and ill-appearing, but is cooperative with her examination. Her skin is jaundiced and there is scleral icterus. Her liver edge is palpable 5 cm below the right costal margin, and is moderately tender. There is no splenomegaly. The rest of her examination, including ophthalmologic, cardiac, pulmonary, and neurological systems, is normal. She has no lymphadenopathy.
Laboratory data: Normal CBC and reticulocyte count. Electrolytes, BUN, and creatinine normal. AST 500, ALT 550, alkaline phosphatase 500, GGT 50, total bilirubin 13.5 (direct fraction 5.0). Prothrombin time is 14.0 seconds (prolonged).
In light of her presentation, additional blood work is sent for anti-HAV IgM, HBsAg, anti-HBc, and HCV. On further questioning, it is discovered she ate at a restaurant one month ago where a worker was found to have hepatitis A. Her blood work later returns positive for hepatitis A.
The liver performs many essential functions. It is the first to receive blood from the intestines through the portal vein. It stores vitamins B12, A, D, E, and K. It also stores glucose in the form of glycogen, or converts it into fatty acids. It deaminizes amino acids into ammonia, which is then converted into urea. It manufactures proteins such as albumin, prothrombin, fibrinogen, transferrin, and glycoprotein from amino acids. The cytochrome P-450 system is responsible for the detoxification of many different compounds (e.g., drugs), and is important in the metabolism of steroid hormones and fatty acids. It also synthesizes bile and plays an important role in lipid metabolism. It excretes bilirubin and biliverdin formed from heme in red blood cells from the reticuloendothelial system in different parts of the body (1). Therefore, diseases that damage the liver can have a very detrimental effect on the body. This chapter will discuss some of the diseases that affect the liver, focusing on viral hepatitis.
Hepatitis is an inflammation of the liver and can be due to many different causes. Although viral hepatitis is well known, other diseases include autoimmune causes such as systemic lupus erythematosus, drug-induced causes such as isoniazid, and metabolic disorders such as Wilson disease, alpha-1-antitrypsin deficiency, tyrosinemia, Niemann-Pick disease type 2, glycogen storage disease type IV, cystic fibrosis, galactosemia, and bile acid biosynthetic abnormalities (2). The anatomy and physiology of the liver is complex and outside the scope of this chapter, although its basic concepts are important to understand the pathophysiology of liver disease. The common theme is that there is injury or death to the hepatocytes. When this occurs, enzymes in these cells are released, which include the aminotransferases (aspartate aminotransferase and alanine aminotransferase), alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT). It should be noted that these aminotransferases are also located in heart and skeletal muscle tissues, although alanine aminotransferase (ALT) is more specific to the liver than aspartate aminotransferase (AST) and has a longer plasma half-life (which makes an elevation of AST indicative of early hepatic damage). Alkaline phosphatase, besides being found in the liver, is also present in kidney, bone, placenta, and intestine. GGT is found in biliary epithelia and hepatocytes, and is therefore a more specific marker for liver disease (3). A misnomer is that liver function tests (LFT's) consists of measuring the levels of aminotransferases, alkaline phosphatase, and GGT. However, these intracellular liver enzymes are not indicative of liver function, but rather damage to the liver. As was mentioned earlier, the liver has many functions, such as the production of proteins from amino acids, gluconeogenesis and glycogenolysis, and the excretion of bilirubin. Therefore, damage to the hepatocytes will result in decreased production of proteins, notably albumin, prothrombin, fibrinogen, glycoproteins, lipoproteins, and enzymes. Low albumin can result in ascites, and low prothrombin, fibrinogen, and other clotting factors can lead to a hypocoagulable state. Hypoglycemia can result from failure of the damaged hepatocytes in maintaining glucose homeostasis (4). A major function of the hepatocyte is the conjugation of bilirubin and its excretion into the bile canaliculi. A sign of hepatic injury is not elevated unconjugated bilirubin, but rather conjugated hyperbilirubinemia, which may be due to the decreased excretion of conjugated bilirubin (cholestasis) due to inflammation around the canaliculi. The build up of bilirubin in the bloodstream leads to jaundice or icterus, which is a yellow coloring of the skin and sclera (of note, scleral icterus can be seen when the bilirubin level exceeds 2.5 mg/dl) (5). Note that only some patients with hepatitis are jaundiced because only some patients develop cholestasis. Ammonia is a normal byproduct of protein degradation by intestinal bacteria, of deamination processes in the liver, and glutamine hydrolysis in the kidneys. The liver metabolizes this toxic ammonia into urea by the Krebs-Henseleit cycle. With hepatic injury, however, the ammonia may accumulate which can lead to encephalopathy and coma (6).
With this short explanation on the pathophysiology of hepatic parenchymal injury, the diseases that cause hepatitis can be more readily understood. This next section will focus primarily on viral hepatitis, in addition to two major causes of metabolic diseases of the liver: Wilson disease and alpha-1-antitrypsin deficiency.
The viral causes of hepatitis can be divided into hepatotropic and non-hepatotropic viruses. The non-hepatotropic viruses include measles, rubella, enteroviruses (coxsackie and echo), flaviviruses (yellow fever, Dengue fever), filoviruses (Marburg and Ebola), arenaviruses (Lassa fever), parvovirus B19, adenovirus, and herpesviruses (herpes simplex types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpes virus type 6) (7). The hepatotropic viruses are fewer in number and consist of hepatitis A, B, C, D, E, and G. The hepatitis viruses important in clinical medicine are hepatitis A, B, C, and delta.
Hepatitis A (HAV) is a picornavirus (single-stranded RNA virus) and is transmitted via the fecal-oral route. After it is ingested, it replicates in the small intestine, and then travels to the liver via the portal vein, where it attaches to hepatocytes via a receptor on the hepatocyte membrane. The replicated HAV is then excreted in the bile and passed on in the feces. Liver injury is thought to be due to a T-cell mediated destruction of hepatocytes, rather than to a direct cytotoxic effect. Important risk factors for acquiring HAV infection are close contact (including sexual), fecal-oral (i.e., poor hand washing, etc.), travel to developing countries, and intravenous drug abuse. Therefore, parenteral transmission of HAV is possible, although uncommon. The incubation period of HAV is 15 to 40 days, with a mean of 28 days, after which the patient can develop clinical manifestations of hepatitis. In older children and adults, symptoms can include fever, anorexia, nausea and vomiting, right upper quadrant abdominal pain, dark urine, and jaundice. Less common symptoms include headache, myalgias, arthralgias, pruritus, and rash. Signs can include hepatosplenomegaly, leukopenia, cervical lymphadenopathy, hyperbilirubinemia, and elevation of serum aminotransferase levels. Fulminant hepatic failure is rare. In infants and younger children, HAV can be asymptomatic or present with "stomach-flu symptoms" of nausea, vomiting, and diarrhea without icterus; therefore suspicion of hepatitis in these patients is often low. Diagnosis is made by measuring anti-IgG and anti-IgM HAV titers. Anti-IgM is present in the acute period, peaking at 1 week and disappearing 3 to 6 months later. Anti-IgG appears later and is highest at 1 to 2 months and lasts for years, and therefore signifies convalescence or immunity. The treatment for HAV is mainly supportive, and the prognosis is good in that it is acute and self-limiting. It does not lead to chronic hepatitis or chronic carriage. In a small percentage of patients, HAV infection can be relapsing or protracted. Prevention consists of good hygiene, the administration of immunoglobulin prophylaxis to contacts, and active vaccination (8,9). Intramuscular immunoglobulin when given as postexposure prophylaxis has >85% effectiveness in preventing symptomatic infection if given in the first 2 weeks of exposure; however, its immunity is short-lived. Active HAV vaccination is recommended for preexposure prophylaxis to people traveling to foreign countries with a high rate of HAV (excludes Australia, Canada, Japan, New Zealand, Western Europe, and Scandinavia). Other recommendations for vaccination are children living in areas of the United States with an incidence rate twice the national average (which includes Arizona, Alaska, Oregon, New Mexico, Utah, Washington, Oklahoma, South Dakota, Idaho, Nevada, and California), people with chronic liver disease, homosexual and bisexual men, IV drug users, patients with clotting-factor disorders, and those who are at risk for occupational exposure) (10).
Hepatitis B (HBV) is a DNA virus in the family hepadnaviridae and has a unique structure. It consists of two shells, of which the outer shell contains the hepatitis B surface antigen (HBsAg) and the inner shell contains the hepatitis B core antigen (HBcAg). In the core are the viral DNA and the hepatitis B e antigen (HBeAg) which is a derivative of the precore DNA region of the HBcAg gene. Like the hepatitis A virus, it has a high affinity for hepatocytes and causes destruction through T-cell mediated cell destruction. HBV is transmitted parenterally and is found in all bodily fluids, but is not found in feces. Although it is found in saliva, the chances of acquiring HBV through sharing of toys by young children are small. Sexual intercourse and vertical transmission (from mother to infant) are other important routes of transmission. Vertical transmission, which is a major cause of acquiring HBV in endemic countries, can occur through the infant swallowing maternal blood during birth or transplacentally. In addition, infants who acquire HBV perinatally have a high risk for chronic hepatitis infection, cirrhosis, and hepatocellular carcinoma. The incubation period is from 50 to 180 days. The clinical course has three stages: prodromal (incubation) stage, symptomatic (icteric) stage, and convalescent stage. The prodromal stage lasts for 2 to 3 weeks and although in most cases the patient is asymptomatic, it can rarely present with membranous nephropathy and vasculitic syndromes. This is followed by the symptomatic (icteric) stage that consists of fatigue, fever, myalgias, anorexia, pruritus, nausea, vomiting, and abdominal pain. This stage can last for 4 to 6 weeks. An interesting dermatologic phenomenon that can occur is papular acrodermatitis of childhood (Gianotti-Crosti syndrome), which presents as nonpruritic symmetrical lichenoid papules on the face, buttocks, and extremities that last for 2 to 3 weeks and often preceded by lymphadenopathy, hepatomegaly, and occasionally splenomegaly (11). The extrahepatic manifestations are possibly due to immune complexes of HBsAg and anti-HBs. After this stage is the convalescent stage (8).
The diagnosis of HBV is made by interpretation of serological markers of HBsAg, HBeAg, anti-HBe, anti-HBc, and anti-HBs, (note the absence of HBcAg which can only be assayed on a liver biopsy, since it does not circulate in the blood in appreciable quantities) and the patient's clinical state. It would be helpful to look at a graph of these markers and course of disease for a visual depiction. However, these graphs are confusing to most students so it would be better to understand where these markers are from and their immunologic/clinical consequence. After inoculation, viral replication occurs. So during incubation and replication of the virus, one would find viral antigens in the serum, namely HBsAg and HBeAg. In fact, these antigens are not found in the blood until 1 to 3 months after the person becomes infected. Patients with these circulating antigens are potentially contagious. A positive HBsAg together with a positive HBeAg is associated with a higher degree of contagiousness than a positive HBsAg alone. While the patient has these antigens then, he is infected and is either in the incubation or symptomatic stage of the disease (acute or chronic). In the meantime, the immune system is fighting off this infection with the production of antibodies against these antigens. For example, Anti-HBs is made in response to HBsAg. The antibody and antigen should not be detectable in the blood stream simultaneously. Basically, the presence of HBsAg indicates infection and contagiousness, while the presence of anti-HBs indicates the presence of immunity. However, there is a brief period after the HBsAg declines and before the anti-HBs rises, when both of them are non-detectable (negative), which is called the "window phase". Anti-HBc is always positive during this window phase.
In acute HBV infection, HBsAg and HBeAg are present. If recovery and immunity are to follow, both antigen levels decline as anti-HBc and anti-HBe levels rise. Ultimately, the presence of anti-HBs signifies immunity. In chronic HBV infection, HBsAg persists and anti-HBs fails to develop. Once anti-HBs and/or anti-HBc are present, these can be fractionated to IgM and IgG. IgM signifies an early immune response, while IgG signifies a later or booster response. It may be best to understand these antigens and antibodies in relation to specific clinical questions.
Is the patient immune or contagious? If the HBsAg is positive, the patient is contagious. If the HBsAb is positive, the patient is immune.
Is a pregnant mother at risk for passing HBV to her child at birth? If mother's HBsAg is positive, then perinatal transmission of HBV is possible and the newborn must receive HBV prophylaxis. If the HBsAg is negative, there is no risk.
The patient is contagious (i.e., the HBsAg is positive), but how contagious is he? If the HBeAg is positive, he is very contagious. If the anti-HBe is positive, then he is less contagious.
Has the patient been exposed to HBV in the past? Check the HBsAg, anti-HBc and anti-HBs. If all of these are negative, the patient has never been exposed to HBV. If one or more are positive, then the patient has been exposed to HBV.
A hepatitis B vaccine recipient wants to confirm immunity. If the anti-HBs is positive, he is immune. If not, immunity has not yet developed.
The prognosis of HBV infection is variable and depends on immune and genetic factors, the age of the patient, and serologic stage of infection. The risk for chronicity increases when primary infection is acquired in the neonatal period compared to adults. For instance, 95% of neonates become chronic carriers, compared to 20% of children, and less than 10% of adults. Chronic states can range from chronic active hepatitis to a chronic non-symptomatic carrier state. Also, the risk for hepatocellular carcinoma (HCC) increases with chronicity; therefore, patients who develop HBV in the neonatal period have the highest risk of developing liver cancer compared to other age groups. It has been shown that men who develop HBV at birth have a 50% lifetime risk for developing HCC compared to women who have a 20% lifetime risk. Patients who develop HCC have a poor prognosis, which has a less than 5% 5-year survival rate (8).
Fortunately, the risk of HBV has declined with universal immunization and diligent prenatal screening. Infants who are born to HBsAg-negative women are given the routine 3-dose hepatitis B immunization, with preterm infants given the first dose after they reach 2 kg. However, newborns from HBsAg-positive women are given both the hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) as postexposure prophylaxis within 12 hours of birth regardless of their birth weight. For infants less than 2 kg, the initial dose should not be counted in the 3-dose schedule (i.e., they are given 4 doses). After completion of the HBV vaccine series, these infants born to HBsAg positive mothers should be tested serologically for anti-HBs and HBsAg 1-3 months after the last dose. For infants who have low anti-HBs (<10 mIU/ml) and negative HBsAg, they should receive 3 additional doses of vaccine at a 0, 1, and 6-month schedule, with anti-HBs testing done 1 month later to determine immunity. If the HBsAg status of the mother is unknown, serologic testing on the mother should be performed as soon as possible. Term infants should receive the hepatitis B vaccine within 12 hours of birth. HBIG does not need to be given unless the mother's serology returns as being HBsAg positive, in which case HBIG is given soon after. Two hepatitis B vaccines are currently available (Recombivax and Engerix). The schedule consists of 3 doses, with the first dose being given soon after birth, a second dose at least 1 month later, and the third dose when the infant is at least 6 months old or at least 2 months after the second dose and at least 4 months after the first dose (12,13). HBV vaccine is also available in a combination vaccine with diphtheria-tetanus-pertussis (DTaP) and inactivated polio vaccine (IPV).
Hepatitis C was a major cause of post-transfusion hepatitis in the past and was known as non-A, non-B hepatitis prior to the late 1980's. It belongs to the family flaviviridae, which are enveloped RNA viruses. It is spread parentally with highest risk factors being illicit intravenous drug use and unprotected sexual intercourse. Although it is an important cause of posttransfusion hepatitis, only 5 to 10% of HCV infections are due to transfusions. Another risk factor is needlestick injuries in hospital workers. Vertical (perinatal) transmission is probably the most common cause of HCV in children, although overall, it is uncommon for an infant to acquire HCV compared to HBV. HCV is thought to have a direct cytotoxic effect, which is in contrast to HAV and HBV. Clinical manifestations are the same for the other forms of hepatitis B, with most cases being anicteric. However, unique features are fluctuating or polyphasic levels of aminotransferases during the course of disease and slow resolution. In 50% of individuals, chronic HCV infection can occur. Out of this 50%, half become chronic carriers and the other half progress to chronic active infection or chronic persistent infection. For those who are chronic carriers, they are asymptomatic although test positive for HCV. For those who develop chronic infection, 20% will develop cirrhosis and are at high risk for hepatocellular carcinoma. There is no vaccine available against HCV due to its high rates of mutation in its viral envelope, although children who do develop HCV infection have been treated successfully with interferon alpha (8,14).
Hepatitis D virus (HDV) or delta agent is a satellite virus, meaning that it can only cause disease, not by itself, but in conjunction with another virus, which in this case is hepatitis B virus. HDV is a very small RNA virus and is thought to damage hepatocytes by a direct cytotoxic effect. Like HBV, it is spread parenterally. Unfortunately, those patients with HBV who are co-infected with HDV have severe forms of hepatitis. Mortality is higher at 2% to 20% compared to less than 1% for those with only HBV infection. Most patients (about three-quarters) with chronic HDV infection develop cirrhosis and portal hypertension (8).
Two forms of metabolic liver diseases will be discussed next: Wilson disease and alpha-1-antitrypsin deficiency. Wilson disease or hepatolenticular degeneration is a disease of copper metabolism. It is autosomal recessive with the affected gene, ATP7B, being on the long arm of chromosome 13. It occurs worldwide, with a prevalence of about 1 in 30,000, with higher rates in consanguineous families. Mutations in this gene cause impaired copper excretion from the hepatocyte to bile, and decreased incorporation of copper into ceruloplasmin in the hepatocyte leading to high serum copper levels and deposition of copper in many organs. The clinical manifestations of Wilson disease rarely appear until 5 years of age, at which time the gradual build up of copper in various organs becomes symptomatic. Dangerous levels of copper become present in the liver, nervous system, cornea, kidneys, and other organs leading to hepatitis, neuropsychiatric symptoms (some of which are tremor, clumsiness, ataxia, headaches, seizures, and dementia), and Kayser-Fleischer rings around the corneas (a greenish-brown ring in Descemet's membrane at the periphery of the cornea). The diagnosis is made on the basis of several tests and clinical data. Serum ceruloplasmin is low (<20 mg/dl), hepatic copper concentration is high (>250 mcg/gm of dry wt.), 24-hour urine copper excretion is high (>100 mcg/24 hours), Kayser-Fleischer rings are present, and incorporation of 64Cu into ceruloplasmin is low. Without treatment, Wilson disease is fatal; therefore, the basis of therapy targets the reduction of stored copper and preventing reaccumulation of copper. This is done by using copper-chelating agents (e.g., D-penicillamine, trientine, zinc acetate, ammonium tetrathiomolybdate, and vitamin D), a low copper diet, oral zinc therapy, and possibly antioxidants (15).
Alpha-1-antitrypsin deficiency (A1AT deficiency) is another important metabolic liver disease that is autosomal recessive and occurs in 1 in 1,600 to 2,000 live births. Alpha-1-antitrypsin is a glycoprotein that inhibits neutrophil proteases such as neutrophil elastase, cathepsin G, and proteinase 3. The absence of alpha-1-antitrypsin allows these dangerous enzymes to cause damage to organs. The two organs that are affected are the liver and lung. Hepatic manifestations include prolonged jaundice in infants; neonatal hepatitis syndrome, and mild elevations of aminotransferases in toddlers; portal hypertension and severe liver dysfunction in older children; chronic hepatitis, cryptogenic cirrhosis, and hepatocellular carcinoma in adults. The pulmonary manifestation is emphysema, although this commonly occurs in adult cigarette smokers and rarely in children. A1AT deficiency is suspected in infants with neonatal jaundice or older children and adults with unexplained chronic liver disease. The diagnosis is made by determining the phenotype of serum alpha-1-antitrypsin by electrophoresis or isoelectric focusing, and confirmation by liver biopsy. The phenotype associated with liver disease is an individual homozygous for PiZZ (ZZ phenotype of the protease inhibitor system). The treatment of liver disease is by liver transplantation, and emphysema with lung transplantation and cessation of cigarette smoking. Gene therapy may be possible in the future (16, 17).
Lastly, the work-up of hepatitis should be done in a systematic and stepwise fashion. Initially, a complete blood count, total and fractionated serum bilirubins, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and prothrombin time (PT) should be performed. AST, ALT, and GGT assess for hepatocellular damage (one could argue that only one of these is necessary) and PT is the most useful test to determine if liver dysfunction is present. If these tests are abnormal and the etiology is unknown, viral hepatitis titers consisting of anti-HAV IgM, HBsAg, anti-HBc, and anti-HCV should be performed. If these tests are negative, other viruses such as Epstein-Barr virus and cytomegalovirus should be considered. If these tests are still negative, other etiologies should be sought after. These etiologies include biliary atresia in neonates (refer to the chapter on biliary atresia), Wilson disease by ceruloplasmin and 24-hour urinary copper excretion, cystic fibrosis by sweat chloride, tyrosinemia by urinary succinyl acetone, alpha-1-antitrypsin deficiency by serum alpha-1-antitrypsin and protease inhibitor phenotyping, and autoimmune hepatitis by presence of autoantibodies and hypergammaglobulinemia (18).
In summary, although viral hepatitis can be self-limited, hepatitis B, C, and delta can cause cirrhosis, death, and liver cancer. Despite the nature of these infections, excellent vaccines can prevent the most common one, hepatitis B. In fact, the hepatitis B vaccine is unique in that it is the only vaccine that can prevent cancer. With the advent of new technologies and gene therapies on the horizon, the outlook for liver disease is favorable.
1. Why are aminotransferases, alkaline phosphatase, and GGT not considered liver function tests? What is the most useful test for liver function?
2. True/False: Most infants and young children with hepatitis A present with jaundice.
3. A family is planning a vacation in China that is known to have a high rate of hepatitis A. How would you give preexposure prophylaxis to this family who has a 15 month old and a 5 year old child?
4. A labor and delivery nurse informs you that a term infant was just born whose mother is HBsAg negative and anti-HBs positive. How would you approach this infant for prophylaxis?
5. A 1600 gm infant is born to a mother who is HBsAg positive, anti-HBc positive, and anti-HBs negative. The NICU nurse is asking what your order is for this patient. Out of these three HepB tests, which one is the most useful in your decision making process.
6. Name three organ systems involved in Wilson disease and its manifestations.
7. What element is implicated in Wilson disease?
8. What organ systems are involved in alpha-1-antitrypsin deficiency and what are their manifestations?
1. Davis FA. Taber's Cyclopedic Dictionary, 16th edition. 1985, Philadelphia: F.A. Davis Company, pp. 450, 1044.
2. Shneider BL, Suchy FJ. Chapter 361-Autoimmune Hepatitis. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1216-1218.
3. Kelly DA. Chapter 1-Useful Investigations in the Assessment of Liver Disease. In: Kelly DA. Diseases of the Liver and Biliary System in Children. 1999, Massachusetts: Blackwell Science, Ltd., pp. 3-10.
4. Colon AR. Chapter 2-General Considerations. In: Colon AR (ed). Textbook of Pediatric Hepatology, 2nd edition. 1990, Massachusetts: Year Book Medical Publishers, Inc., pp. 6-15.
5. Colon AR. Chapter 3-Signs and Symptoms. In: Colon AR (ed). Textbook of Pediatric Hepatology, 2nd edition. 1990, Massachusetts: Year Book Medical Publishers, Inc., pp. 16-29.
6. Colon AR. Chapter 4-Diagnostic Aids. In: Colon AR (ed). Textbook of Pediatric Hepatology, 2nd edition. 1990, Massachusetts: Year Book Medical Publishers, Inc., pp. 30-47.
7. Davison S. Chapter 4-Acute Hepatitis. In: Kelly DA (ed). Diseases of the Liver and Biliary System in Children. 1999, Massachusetts: Blackwell Science, Ltd., pp. 65-76.
8. Yazigi NA, Balistreri WF. Chapter 17-Acute and Chronic Viral Hepatitis. In: Suchy FJ, Sokol RJ, Balistreri WF (eds). Liver Disease in Children, 2nd edition. 2001, Philadelphia: Lippincott Williams & Wilkins, pp. 365-428.
9. Tanuos H. Hepatitis A. Pediatr Rev 1999;20 (3):102.
10. American Academy of Pediatrics. Hepatitis A. In: Red Book 2000, 25th edition. 2000, Illinois: American Academy of Pediatrics, pp. 280-289.
11. Hurwitz S. Chapter 5-Papulosquamous and Related Disorders. In: Hurwitz S. Clinical Pediatric Dermatology, 2nd edition. 1993, Philadelphia: W.B. Saunders Company, pp. 105-135.
12. American Academy of Pediatrics. Hepatitis B. In: Red Book 2000, 25th edition. 2000, Illinois: American Academy of Pediatrics, pp. 289-302.
13. Centers for Disease Control and Prevention. Chapter 14-Hepatitis B. In: Atkinson W, Wolfe C, Huminston S, Nelson R (eds). Epidemiology and Prevention of Vaccine-Preventable Diseases, 6th edition. 2000, Atlanta: Public Health Foundation, pp. 207-229.
14. Rajan-Mohandas N. Hepatitis C. Pediatr Rev 1999;20(9):323.
15. Sokol RJ, Narkewicz MR. Chapter 26-Copper and Iron Storage Disorders. In: Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in Children, 2nd edition. 2001, Philadelphia: Lippincott Williams & Wilkins, pp. 595-640.
16. Perlmutter DH. Chapter 23-Alpha-1-Antitrypsin Deficiency. In: Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in Children, 2nd edition. 2001, Philadelphia: Lippincott Williams & Wilkins, pp. 523-548.
17. Balistreri WF. Chapter 357-Metabolic Diseases of the Liver. In: Behrman, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1207-1212.
18. Rosenthal P, Lightdale JR. Laboratory Evaluation of Hepatitis. Pediatr Rev 2000;21(5):178.
Answers to questions
1. These enzymes are found within the hepatocyte, and therefore are indicative of hepatocellular damage, and not actual function of the liver. The most useful test for liver function is prothrombin time.
2. False. They are usually anicteric.
3. The 15 month old should receive immunoglobulin (too young to receive Hep A vaccine). The 5 year old can receive the Hep A vaccine since she is over 2 years of age. The vaccine is given as two doses 6 months apart.
4. The mother is actually immune to hepatitis B, perhaps from receiving hepatitis B vaccinations in the past or from a previous exposure to hepatitis B. She does not have infection, she is not contagious and in fact, she is immune. This infant does not need HBIG prophylaxis, but should be vaccinated against hepatitis B in the usual fashion.
5. The mother has a positive HBsAg, which means that she is contagious. Therefore, this infant needs HBIG and hepatitis B vaccine prior to 12 hours of age. Because this premie is less than 2 kg, a 3-dose vaccine schedule should be instituted after this infant is over 2 kg, and not counting the initial dose because he was less than 2 kg. After completion of the 3-dose schedule, he should be tested serologically for anti-HBs and HBsAg 1-3 months after completion of the series. If his anti-HBs (<10 mIU/ml) is low and HBsAg is negative, then he should receive 3 additional doses of vaccine at a 0, 1, and 6-month schedule, with anti-HBs testing done 1 month later to determine immunity. The mother's status could be consistent with acute hepatitis B, chronic hepatitis B, or a hepatitis B carrier state. The most important serologic test out of the three listed is the HBsAg, since this test tells us whether the mother is contagious and the newborn requires HBIG prophylaxis.
6. Brain (or nervous system), liver, and eye. Manifestations are neuropsychiatric symptoms, hepatitis, and Kayser-Fleischer rings.
8. Lung and liver. The pulmonary manifestation is emphysema and hepatic manifestations include prolonged jaundice in infants, neonatal hepatitis syndrome, mild elevations of aminotransferases in toddlers, portal hypertension and severe liver dysfunction in older children, and chronic hepatitis, cryptogenic cirrhosis, and hepatocellular carcinoma in adults.