Management of Hepatitis C in Children – A New Paradigm

Introduction: With the advent of direct-acting antivirals (DAAs), the past decade has seen a paradigm shift in the management of hepatitis C (HCV) infection in children. In this review, we summarize the various treatment options for pediatric HCV infection, highlighting the recent changes in the management. Methods: A literature search was performed using the PubMed database with the relevant keywords. Filters included were human, ages 0-18 years, and the English language. Results: Initial phase of HCV treatment using conventional or pegylated interferon and ribavirin combination regimens yielded poor outcomes in children, especially in genotypes 1 and 4, with an overall sustained virologic response of 58%. Also, treatment with interferon and ribavirin combination was associated with significant side effects in up to 52% of those treated. Presently, various combinations of direct-acting antivirals (DAAs) have been approved in children above three years of age with documented evidence of high efficacy (SVR12 of 92% to 100%) and excellent safety, and the current standard of care. Conclusion: With various DAA regimens now being approved for children above three years of age, the treatment of active HCV infection (HCV-RNA positive) in children has become simple. Besides the effectiveness of DAA therapy, public awareness about HCV transmission, better screening, and making the DAAs available at a subsidized price in the public sectors are necessary to eliminate HCV infection in India.

Approach to Constipation in Children.

Purpose: There is a scarcity of literature, and prevalent misconceptions about constipation in India. Methods: A literature search in PubMed was conducted with regard to epidemiology, clinical features, and management of constipation. Special emphasis was paid to functional constipation and refractory constipation. English language studies available full text over the last 25 years were considered and relevant information was extracted. Conclusions: Estimated prevalence of constipation is 3% among toddlers and pre-school children worldwide and 95%, of them are considered functional. A careful history and thorough physical examination is all that is required to diagnose functional constipation. Management includes disimpaction followed by maintenance therapy with oral laxative, dietary modification and toilet training. A close and regular follow-up is necessary for successful treatment. In most of the cases laxative needs to be continued for several months and sometimes years. Early withdrawal of laxative is the commonest cause of recurrence. Refractory constipation is less common in primary care set up. Radiological colon transit study is useful in picking up Slow transit constipation. Antegrade continence enema plays an important role in the management of slow transit constipation.

Classical Galactosemia Among Indian Children: Presentation and Outcome from a Pediatric Gastroenterology Center.

Objective: To analyze the presentation and predictors of outcome of children with galactosemia. Methods: Analysis of clinical, laboratory, microbiological profile and outcome of patients fulfilling the diagnostic criteria: i) clinical setting; ii) reduced erythrocyte Gal-1-PUT enzyme activity; and iii) unequivocal response to lactose-free diet. Results: 24 patients; median age of symptom onset and diagnosis: 10 (3-75) d and 55 (15-455) days, respectively. 71% had uncorrectable coagulopathy; 71% systemic infections; and 54% had ascites. Outcome: consisted of 87.5% survival with normalization of liver function tests at 5.5 (1-24) months follow-up. Conclusion: Despite delayed referral, high Pediatric end-stage liver disease scores and systemic infections, long-term outcome in galactosemia is rewarding. A subset of children have developmental delay.

Diagnosis and Management of Gastroesophageal Reflux Disease (GERD): An Indian Perspective.

Need and Purpose: The scarcity of literature and lack of published guidelines on gastroesophageal reflux disease (GERD) from India, have necessitated this review. Methods: A literature search in PubMed was conducted with regard to epidemiology, clinical features, investigation and management of GERD in children. English language studies published full over the last 20 years were considered and relevant information was extracted. Results: Nearly half of all healthy babies regurgitate at least once a day by 4 months of age and this subsides in 90% of them by 1 year. In contrast, GERD prevalence increases with age and by adolescence it is similar to adults (20%). While regurgitation in infancy does not need investigation or therapy, ‘empirical’ proton pump inhibitor (PPI) for 4 weeks is justified in older children with classical GERD symptoms. There is no gold-standard investigation for GERD. A pH study with or without impedance is useful in extraesophageal manifestations and endoscopy in esophagitis. Proton pump inhibitors (PPI) play a pivotal role in the management of GERD and its long-term use has been shown to be safe in children. Antireflux surgery plays a minor role due to, its associated morbidity and high failure rate, especially in the high risk group who needs it most. Conclusions: Regurgitation in infancy need not be investigated unless there are warning features. Empirical PPI therapy is justified in older children and adolescents with typical reflux symptoms. pH study in extraesophageal manifestations and endoscopy for esophagitis are the investigations of choice. PPI is the mainstay of therapy in GERD.

Management of extra hepatic portal venous obstruction (EHPVO): current strategies.

Extrahepatic portal venous obstruction (EHPVO) is the commonest cause of portal hypertension and variceal bleeding in children. Though mortality related to variceal bleeding is uncommon, morbidity due to massive splenomegaly with hypersplenism, growth failure, ectopic varices like rectal varices and portal biliopathy is significant. A significant proportion of cases in adults are due to procoagulant state but the same has not been documented in children. Studies in children have shown that hereditary or acquired coagulation disorders do not play a role in the pathogenesis of EHPVO in children. Regarding endotherapy for variceal bleeding, there is no doubt that band ligation is superior to sclerotherapy. Nevertheless, a combination of band ligation followed by sclerotherapy has shown to be superior to either modality in children with EHPVO. Growth retardation due to growth hormone resistance is common in children with EHPVO. Diminished portal blood flow results in decreased insulin delivery to the liver and thereby decreased production of insulin-like growth factor-1 (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). Improvement of growth after restoration of hepatic blood flow with mesenteric-left-portal bypass or Rex shunt, has been documented. Portal biliopathy is universal in adults and common in children but symptomatic cases are mainly in adults; thereby suggesting a progressive nature of the condition. Symptomatic biliary obstruction can be managed endoscopically but shunt surgery followed by biliary bypass (if necessary) seems to be the best management option. With the availability of the most physiological shunt (mesenteric-left-portal bypass or Rex) the management paradigm of EHPVO has changed from endotherapy to primary shunt surgery.

Gallstone Disease in Children.

Context: Little is known about the epidemiology of cholelithiasis in children. Cholelithiasis and choledocholithiasis were considered to be uncommon in infants and children but have been increasingly diagnosed in recent years due to widespread use of ultrasonography. However, there is not much of information from India and no consensus among Indian pediatricians and pediatric surgeons regarding management of gallstones in children. Hence, the purpose of this review is to increase awareness about the management of gallstones in children. Methods: Extensive electronic (PubMed) literature search was made for this purpose and literature (original articles, clinical trials, case series, review articles) related to gallstones in children were reviewed. Conclusions: The etiologies of cholelithiasis are hemolytic (20%-30%), other known etiology (40%-50%) such as total parenteral nutrition, ileal disease, congenital biliary diseases, and idiopathic (30-40 %). Spontaneous resolution of gallstones is frequent in infants and hence a period of observation is recommended even for choledocholithiasis. Children with gallstones can present with typical biliary symptoms (50%), nonspecific symptoms (25%), be asymptomatic (20%) or complicated (5%-10%). Cholecystectomy is useful in children with typical biliary symptoms but is not recommended in those with non-specific symptoms. Prophylactic cholecystectomy is recommended in children with hemolytic disorders.

Role of IgG anti-beta-lactoglobulin antibody in the diagnosis of cow's milk protein intolerance in India.

OBJECTIVE: Little is known about cow's milk protein intolerance (CMPI) in India. This study was aimed at finding CMPI cases and determining the role of IgG anti-beta-lactoglobulin antibody in the diagnosis of this condition in India. METHODS: From June 2004 to December 2005, 30 children with presumptive diagnosis of CMPI, based on endoscopic rectal or duodenal biopsy showing excess eosinophils and response to milk withdrawal, were enrolled and studied prospectively. Definite diagnosis was made in 20 children on the basis of positive milk challenge. IgG anti-beta-lactoglobulin antibodies were tested in children with CMPI before and after stopping milk and after milk challenge. Antibody levels were also studied in 27 age-matched disease controls and 50 healthy adults. RESULTS: The median age of 20 children (16 boys) with CMPI was 16.5 (6-36) months. Of them, 18 presented with diarrhea (12 bloody) and 2 had rectal bleeding. The presumptive diagnosis was most often (85%) based on colonic or rectal biopsy findings. Rectal biopsy was diagnostic in all 20 cases irrespective of the mode of presentation compared with duodenal biopsy which was diagnostic in 3 cases (p< 0.0001). There was no difference in antibody levels between cases and controls; the antibody level decreased significantly after milk withdrawal (p< 0.005), but did not rise significantly after milk re-challenge. CONCLUSIONS: CMPI is a common cause of chronic diarrhea in children in northern India. Sigmoidoscopy and rectal biopsy help in establishing the diagnosis in most cases. IgG anti-lactoglobulin antibody test is not useful in diagnosing CMPI in the Indian setting.

Time to recognize atypical celiac disease in Indian children.

BACKGROUND/OBJECTIVE: There is scant information about atypical (non-diarrheal) presentation of celiac disease (CD) from India. We conducted this study to compare non-diarrheal and diarrheal presentations of CD in children. METHODS: From November 2003 to December 2005, we prospectively screened two groups of children for CD, group I with diarrhea and group II without diarrhea but with atypical presentations (unexplained growth retardation, refractory anemia, refractory rickets, chronic constipation and abdominal distension). Screening was done with IgA antiendomysial antibody (EMA) followed by duodenal biopsy if EMA was positive. Celiac disease was diagnosed according to modified ESPGHAN criteria. RESULTS: A total of 200 children were screened (103 in group I and 97 in group II) and CD was diagnosed in 42 (classical 24, atypical 18). Presentation of atypical CD were; short stature 6, anemia 4, abdominal distension 3, rickets 2, and constipation, diabetes mellitus, delayed puberty in 1 case each. Patients with atypical CD were older (median age 10.4 years vs 5.5 years, p< 0.007) than classical cases. On mean (SD) follow-up of 12.6 (7.5) months all showed response to gluten-free-diet, and median gain in weight, height and final hemoglobin levels were similar in the two groups. CONCLUSION: Atypical CD is not uncommon in India. Children with atypical CD present at an older age. Likelihood of finding CD is high in children with anemia, short stature and rickets.

Helicobacter pylori in children: an Indian perspective.

Helicobacter pylori is causally associated with peptic ulcer disease and gastric carcinoma. Typically children get infected with this organism during the first decade of life but diseases, associated with H. pylori, are seen mainly in adults. In India, almost 80% of population is infected with H. pylori and most of them by 10 years of age. Hence, it is important for a pediatrician to know when to suspect this infection, how to investigate and how to treat it. Extensive electronic (PubMed) literature search was done for this review and literature (randomized controlled trials, clinical trials, meta-analysis, practice guidelines) related to H. pylori in children were reviewed. Special emphasis was given to Indian studies. From this review we can conclude that H. pylori infection is very common in Indian children especially in the low socioeconomic status but most infected children remain asymptomatic through out their childhood and about 15% develop peptic ulcer disease as young adults and 1% develop gastric cancer in older age. There is no association, what so ever, of H. pylori infection and recurrent abdominal pain (RAP). Endoscopy is the preferred method of investigation in children with upper digestive symptoms suggestive of organic disease. Children with H. pylori related disease (peptic ulcer, primary gastric B-cell lymphoma and atrophic gastritis with intestinal metaplasia) but not mere H. pylori infection should be treated with the triple drug regimen comprising of proton pump inhibitor (PPI) and two antibiotics for two weeks.

Celiac disease in India.

This review of the current scenario of celiac disease (CD) in India covers both pediatric and adult CD. CD is primarily reported from northern India with isolated case reports from the rest of the country. CD cases among Indian children are associated with multiple DR3-DQ2 haplotypes. Delay in diagnosis is contributed by multiple factors including atypical presentations. Use of serological tests, IgA EMA and anti-tTG antibodies, along with modified ESPGHAN criteria provides a definitive diagnosis of CD. Dietary management is often difficult due to non-availability of labeled and marketed gluten-free foods. A majority of children with CD show normalization of nutrition, substantial improvement in growth parameters and attainment of healthy percentile curves on gluten-free diet. Small bowel histology remarkably improves but does not normalize even after 2-3 years on gluten-free diet. The true burden of the disease should be addressed by large epidemiological studies.

Factor V Leiden and prothrombin gene G20210A mutations are uncommon in portal vein thrombosis in India.

BACKGROUND: Extra-hepatic portal vein obstruction due to portal vein thrombosis (PVT) is an important cause of portal hypertension in several regions including India. The cause of thrombosis in these patients remains unclear. We studied the frequency of mutations in genes for coagulation factors V and II (prothrombin) in 61 Indian patients with PVT and 49 healthy control subjects. METHODS: The presence of factor V Leiden mutation and of G20210A prothrombin gene mutation was determined using polymerase chain reaction followed by restriction fragment length polymorphism. Chi-squared test was used to compare patients and controls. RESULTS: Of the 61 patients (median age 11 years; 47 male) studied, 49 were children. One of 61 (1.6%) patients with PVT was heterozygous for factor V Leiden mutation and none had the G20210 prothrombin gene mutation. The frequencies of these mutations were not different from those in control subjects (2/49 and 0/46, respectively). CONCLUSION: Factor V Leiden and G20210 prothrombin gene mutations are infrequent in Indian patients with PVT. Thus, these mutations are unlikely to be responsible for PVT in the Indian population.