HEPATITIS/OBESITY
From the 38th Annual Advances and Controversies in Clinical Pediatrics, presented June 2-4, 2005, by the
Department of Pediatrics, University of California, San Francisco, School of Medicine
| THE ABCS OF HEPATITIS: A PRACTICAL APPROACH TO COMMUNITY EXPOSURE—Frank R. Sinatra, MD, Professor
of Medicine, Keck School of Medicine at the University of Southern California, Los Angeles
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Hepatitis A Virus (HAV)
| Background: incubation—average 30 days; incidence of jaundice—age dependent; most patients <6 yr of age anicteric;
chances of becoming jaundiced increase with age; complications—does not cause chronic liver disease but can cause
fulminant hepatitis and atypical courses, such as cholestatic hepatitis and relapsing hepatitis; age-specific mortality—
worse for patients <5 yr of age and >30 yr of age; mortality rate rises significantly after 49 yr of age
|
| Strategies for hepatitis A prevention: hygiene (hand washing); sanitation (clean water); pre-exposure immune globulin
(IG) for patients traveling to endemic areas superseded by HAV vaccine; postexposure IG useful for patients with known
exposure, especially if in high-risk group and <2 wk from exposure (not useful ≥2 wk after exposure)
|
| HAV vaccine: licensed in 1995; in 1996, Advisory Committee on Immunization Practices (ACIP) recommended children living
in communities in United States with highest rates of HAV (>20 cases per 100,000 residents) should be considered for vaccination;
in 1999, ACIP recommended that immunization be considered in communities where HAV rate <20 but >10 cases
per 100,000; other indications for HAV immunization—travelers to areas with intermediate or high HAV infection
rates; patients with chronic liver disease, clotting factor disorders, or occupational exposure risk; drug users
|
 | Characteristics: cell culture–adapted virus grown in human fibroblasts; inactivated with formalin; safety—minimal side effects;
safety in pregnancy not determined but probably low; previous reaction to vaccine component only contraindication;
duration of protection—8 yr after 2 doses; simultaneous IG—can be given; seroconversion rates not impaired, but
lower antibody titers may result (not clinically significant); preparations—Havrix and Vaqta equally effective; preferable
to complete series with same product
|
| Impediments to universal HAV immunization: cost—$100 to $150; preimmunization serologic testing may be cost effective if
patient potentially exposed to HAV or who has history suggestive of acute hepatitis A; postimmunization serologic testing
not indicated because of high seroconversion rate; increased office visits—combined HAV and hepatitus B virus (HBV;
Twinrix) available
|
Hepatitis B Virus
| Background: incubation—60 to 90 days (range 45 to 180); incidence of jaundice—<10% of patients <5 yr of age; <50% of
patients >5 yr of age; acute fatality rate—1%; chronic infection—younger age increases likelihood of chronic disease; 30%
to 90% of patients <5 yr of age become chronically infected, compared to 2% to 10% of patients >5 yr of age; 15% to 25% of patients
who acquire HBV have premature mortality related to chronic liver disease; incidence—peak incidence of HBV acquisition
occurs in patients 20 to 30 yr of age, likely by sexual transmission or drug use
|
| Outcome of HBV infection: 90% of patients who acquire HBV during infancy, especially by vertical transmission, develop
chronic disease; likelihood of symptomatic disease (jaundice, overt hepatitis) increases with age
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| Course of disease: majority of patients recover; 10% to 30% of patients develop persistent infection in form of asymptomatic
carrier state or chronic hepatitis, possibly leading to cirrhosis or hepatocellular carcinoma (HCC)
|
| Maternal-neonatal transmission: if mother HBV surface antigen (HBsAg) carrier and HBV e antigen (HBeAg) positive,
likelihood baby will acquire HBV 90% (if mother HBeAg negative, likelihood 20%); mothers who are HBeAg negative
most likely to give birth to babies with acute symptomatic disease; acute hepatitis—during first or second trimester,
likelihood baby will acquire hepatitis B 10%; during third trimester, likelihood 80%
|
| HBV vaccine: available since 1982; current vaccine recombinant preparation made from part of surface protein; does not
contain live components; thimerosal-free vaccine became available in 1999; safety—no evidence of side effects
|
| Benefits of routine HBV vaccination in newborns: immunogenic in newborn; dependable medical encounter; best opportunity
to prevent unrecognized perinatal transmission; emphasizes importance of immunization
|
| Immunizing infants born to HBsAg-negative mothers: can wait until 2-mo visit and use combination vaccine; alternatively,
give HBV vaccination in newborn period and give full immunization during follow-up visit
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| Prevention of vertical transmission of HBV: HBsAg-positive mother—administer hepatitis B IG (HBIG) and HBV vaccine
within first 12 hr; complete immunization series at 1, 2, and 6 mo; measure HBsAg and antihepatitis B surface antibody
between 9 and 15 mo; mothers without prenatal screening—speaker recommends checking maternal HBsAg administering
HBV vaccine, and administering HBIG within 7 days if HBsAg results positive; high-risk mother—treat child as though
HBeAg positive
|
| Treatment of chronic hepatitis B: interferon alfa-2b—6-mo course; 30% of children with elevated transaminases become
HBeAg negative, compared to 10% of untreated controls; lamivudine—23% of children become HBeAg and HBV DNA
negative, compared to 13% of controls; development of viral (YMDD) mutants problematic; licensed for children >2 yr of
age; adefovir—not yet approved for pediatric patients
|
Hepatitis C Virus (HCV)
| Background: in United States, 1.8% of population (4 million people) infected with HCV; 75% of infected people asymptomatic,
especially those who acquired virus by vertical transmission; high rate of chronicity; relatively low progression
to fibrosis and cirrhosis; most common cause of end-stage liver disease; 2% to 6% of patients with hepatitis C develop
HCC during first 20 yr of disease
|
| Incidence of HCV infection in United States: number of cases increased steadily from 1960s until time HCV identified and
blood screening introduced; Donahue et al, 1992—4% of patients receiving blood transfusions between 1985 and 1986
developed hepatitis C; use of surrogate markers and anti-HCV antibody titers led to dramatic decrease in HCV transmission
|
| Vertical transmission: for HIV-negative mothers with hepatitis C, transmission rate 5%; for HIV-positive mothers with
hepatitis C, transmission rate 20%; Conte et al—15,000 pregnant women screened in Italy; 2.4% of participants anti-
HCV positive; 266 participants (1.7%) HCV RNA positive; at 1 yr of age, 5% of newborns acquired hepatitis C and were
HCV RNA positive with same genotype as mother; rate of transmission unaffected by route of delivery, breast-feeding, or
maternal HIV status; risk factors—HCV viremia (transmission unlikely if HCV RNA titer <106 copies/mL); maternal
HIV status; internal fetal monitoring; membrane rupture >6 hr
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| Management of infant born to HCV-positive mother: routine screening of all pregnant women not recommended;
women with risk factors should receive screening; speaker recommends testing infants born to infected mothers at 18 mo
to give time for maternal antibody titers to clear
|
| Breast-feeding: not contraindicated; Centers for Disease Control and Prevention (CDC) and Red Book guidelines state that
mothers infected with HCV can breast-feed, but should abstain if nipples cracked or bleeding
|
| Rate of progression to fibrosis: minimal in 25% to 30% of patients, intermediate in 50% of patients, and rapid in 25%; in
adult studies, alcohol use, older age, male sex, coinfection with HIV or HBV, and increasing hepatic steatosis promote
more rapid progression
|
| Treatment of chronic hepatitis C in children: study—70 children with HCV infection treated for 24 wk with interferon alfa-
2b and ribavirin; 50% of children had sustained virologic response (6 mo after stopping therapy, no HCV RNA could be identified
and transaminases normal); many children experienced adverse side effects; arguments for treatment—early treatment
may prevent cirrhosis; children respond to treatment as well as adults; helps prevent spread of HBV and HCV; arguments
against treatment—most children asymptomatic; fibrosis usually develops slowly, particularly after vertical transmission;
side effects from current therapy significant; success rate 50%; spontaneous resolution occurs in some children
|
| PHARMACOLOGIC AND SURGICAL APPROACHES TO CHILDHOOD OBESITY—Robert H. Lustig, MD, Professor
of Pediatrics, Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, School of
Medicine
|
| Negative plateau in weight loss: in trials of dexfenfluramine, sibutramine, and orlistat, plateau in weight loss reached after
4 mo; effect occurs because body reduces energy expenditure to offset change in caloric intake by decreasing nonexercise-associated
thermogenesis (NEAT) and decreasing resting energy expenditure
|
| Variable response to drugs: noncompliance not an issue; alterations in pharmacokinetics having genetic basis (pharmacogenomics)
likely play role; need to address actual mechanism of obesity; one drug does not fit all
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| Leptin deficiency: adipocyte hormone that informs brain of how thin person may be (“starvation hormone”); each person
has leptin threshold; hypothalamus recognizes any level above threshold as state of energy sufficiency allowing normal
metabolic processes; if leptin level falls below threshold (eg, dieting or by taking weight-loss drug), brain reacts by decreasing
energy expenditure in response to decreased caloric requirement, representing negative plateau; ob mouse—
mouse deficient in leptin, so brain perceives constant state of starvation, leading to continual weight gain until death; leptin
deficiency in humans—family of 11 leptin-deficient patients living in Cambridge, United Kingdom; immediately after
birth, patients’ weights increased dramatically (above 98th percentile); when leptin administered, patients lost weight
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| Leptin resistance: obese patients likely leptin-resistant; leptin increases as percentage of body fat increases, but brain may
perceive lower leptin level than actual; if weight-loss program results in reduced leptin, brain can perceive new level as below
threshold, leading to initiation of starvation response and prevention of further weight loss; study—dose- finding
study of leptin in adult obesity; essentially no weight loss except at highest dose; at highest dose, because of side effects,
only 2 of 18 patients completed study
|
| Sibutramine: Berkowitz et al—double-blind, placebo-controlled trial of behavior therapy with or without sibutramine in 82
obese adolescents; considerable weight loss achieved before reaching plateau at 6 mo; variation in magnitude of response; 19
of 43 participants experienced mild hypertension and tachycardia; 5 required discontinuation; side effects include insomnia,
anxiety, headache, and depression; no data on use in absence of behavioral intervention; drug approved for patients >16 yr of
age
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| Orlistat: “fat blocker”; inhibits pancreatic lipase; prevents breakdown of triglycerides to monoglycerides and fatty acids; triglycerides
cannot be absorbed, lost in stool; McDuffe et al—modest weight loss (2%-3%) achieved in 20 adolescents; variable
response to therapy; company-sponsored trial—534 participants randomized to lifestyle intervention with or without
orlistat; significant results achieved at 4 mo but not 12 mo; variable response and high dropout rate; side effects include deficiencies
of fat-soluble vitamins (especially vitamins A, D, and K), flatulence, diarrhea, and leakage; requires highly motivated
patients; approved for children >12 yr of age
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| Insulin disorders in childhood obesity: insulin resistance—fasting hyperinsulinemia; liver and muscle dysfunction; responsive
to metformin; insulin hypersecretion—postprandial hyperinsulinemia; vagal and pancreatic dysfunction; responsive to
octreotide
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| Metformin: reduces hepatic gluconeogenesis; decreases food intake; reduces fat stores; reduces risk for type 2 diabetes in adults
and appears to have same effect in children; study data—body mass index (BMI; weight [kg]/height [m2 ]) SD scores reduced
by 0.1 at 6 mo; insulin level also reduced; children taking psychotropic drugs—metformin useful in overcoming insulin resistance
induced by drugs such as risperidone, olanzapine, quetiapine, and valproate; predictors of response—metformin
works if patient insulin-resistant but not insulin-sensitive; not effective in blacks due to hypersecretion; side effects—transient
abdominal discomfort or diarrhea; lactic acidosis (rare) due to urinary loss of B vitamins; approved for treatment of type 2 diabetes
but not obesity
|
| Octreotide: reduces insulin secretion from β-cell by blocking voltage-gated calcium channel; used for children with brain
tumors who have defect in transduction of information from hypothalamus to pancreas (vagally-driven insulin hypersecretion);
in such patients taking octreotide, change in weight corresponds well to change in insulin
|
| Bariatric surgery: National Institutes of Health (NIH) guidelines for adolescent bariatric surgery state that adolescents
with BMI between 30 and 40 should receive behavioral therapy only; if BMI >40 with serious comorbidity, bariatric
surgery may be considered; if BMI >50 with or without comorbidity, consider bariatric surgery
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| Laparoscopic adjustable gastric band (LABG): change in estimated weight loss quite good but not immediate; patients do
not appear to regain weight; final excess weight lost comparable to that from gastric bypass
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| Roux-en-Y gastric bypass: decreases size of stomach and causes anastomosis; more extensive operation that requires longer
hospital stay; favored in United States, as surgeons have greater experience with technique; proven effective in adults; mortality
and morbidity rates tenfold higher than LABG
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| Precautions: surgery must be performed in major medical center; close monitoring of protein intake and hydration status; postoperative
visits with surgeon, pediatrician, exercise physiologist, and psychologist; patients must demonstrate compliance
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Educational Objectives
| The goal of this program is to educate the listener about hepatitis and obesity in children and adolescents. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Review the prevalence and prevention of hepatitis A.
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| 2. Discuss the likelihood and prevention of vertical transmission of the hepatitis B virus.
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| 3. Prescribe appropriate management strategies for an infant born to a mother infected with the hepatitis C virus.
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| 4. Describe the role of leptin in obesity.
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| 5. Discuss the role of bariatric surgery in obese adolescents.
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Discussed on This Program
Adefovir dipivoxil [Hepsera]
Hepatitis A vaccine, inactivated [Havrix, Vaqta]
Hepatitis A, inactivated and hepatitis B, recombinant vaccine [Twinrix]
Hepatitis B immune globulin (human) (HBIG) [BayHep B, Nabi-HB]
Hepatitis B vaccine, recombinant [Engerix-B, Recombivax HB]
Interferon alfa-2b (recombinant) (IFN-alpha 2; rIFN-⓬ α-2-interferon) [Intron A]
Lamivudine (3TC) [Epivir, Epivir-HBV]
Metformin HCl [Fortamet, Glucophage, Glucophage XR]
Octreotide acetate [Sandostatin, Sandostatin LAR, Sandostatin LAR Depot]
Orlistat [Xenical]
Sibutramine HCl [Meridia]
Resources
Breast-feeding guidelines for HCV-infected mothers: CDC.gov and aapredbook.aappublications.org
Suggested Reading
Armstrong GL, Bell BP: Hepatitis A virus infections in the United States: model-based estimates and implications for childhood
immunization. Pediatrics 109(5):839, 2002; Berkowitz RI et al: Behavior therapy and sibutramine for the treatment of
adolescent obesity: a randomized controlled trial. JAMA 289(14):1805, 2003; Conte D et al: Prevalence and clinical course of
chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology
31(3):751, 2000; Durant N, Cox J: Current treatment approaches to overweight in adolescents. Curr Opin Pediatr
17(4):454, 2005; Farooqi IS et al: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J
Med 341(12):879, 1999; Farooqi S et al: ob gene mutations and human obesity. Proc Nutr Soc 57(3):471, 1998; Foster GR
et al: Effects of mode of delivery and infant feeding on the risk of mother-to-child transmission of hepatitis C virus. BJOG
110(1):91, 2003; Freemark M, Bursey D: The effects of metformin on body mass index and glucose tolerance in obese adolescents
with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 107(4):E55, 2001; Gouvea AF et
al: Immunogenicity and tolerability of hepatitis A vaccine in HIV-infected children. Clin Infect Dis 41(4):544, 2005; Horgan
S et al: Laparoscopic adjustable gastric banding for the treatment of adolescent morbid obesity in the United States: a safe alternative
to gastric bypass. J Pediatr Surg 40(1):86, 2005; Kurugol Z et al: A two-dose schedule for combined hepatitis A
and B vaccination in children aged 6-15 years. Vaccine 23(22):2876, 2005; Lumb J: HIV and hepatitis co-infection: a consensus
for treatment? Lancet Infect Dis 5(4):202, 2005; Lustig RH et al: Obesity, leptin resistance, and the effects of insulin reduction.
Int J Obes Relat Metab Disord 28(10):1344, 2004; Lustig RH et al: Hypothalamic obesity caused by cranial insult
in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr 135(2 Pt 1):162, 1999;
Maayan-Metzger A et al: To vaccinate or not to vaccinate--that is the question: why are some mothers opposed to giving
their infants hepatitis B vaccine? Vaccine 23(16):1941, 2005; Morrison JA et al: Metformin for weight loss in pediatric patients
taking psychotropic drugs. Am J Psychiatry 159(4):655, 2002; Navas E et al: Efficiency of the incorporation of the
hepatitis A vaccine as a combined A+B vaccine to the hepatitis B vaccination programme of preadolescents in schools. Vaccine
23(17-18):2185, 2005; Van Damme P, Van Herck K: Effect of hepatitis A vaccination programs. JAMA 294(2):246,
2005; Wasley A et al: Incidence of hepatitis A in the United States in the era of vaccination. JAMA 294(2):194, 2005; Zuccotti
GV et al: Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus. J Pediatr
125(1):70, 1994;
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Sinatra has received a research grant from the Schering-Plough Research Institute.
Drs. Sinatra and Lustig were recorded at the 38th Annual Advances and Controversies in Clinical Pediatrics, presented June
2-4, 2005, by the Department of Pediatrics, University of California, San Francisco, School of Medicine. The Audio-Digest Foundation
thanks Drs. Sinatra and Lustig and the University of California, San Francisco, School of Medicine for their cooperation in the production of this program.
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