A recent open-label “NACSTOP trial” (A Wong et al. Hepatology 2019; 69: 774-84) examined a 12-hour regimen of acetylcysteine in patients at lower risk for severe hepatotoxicity from acetaminophen overdose.
Background/Methods: Intravenous acetylcysteine is generally delivered as 300 mg/kg over 20 hours in “nearly every patient deemed at any risk for hepatotoxicity following acetaminophen overdose.” Administration within 8 hors of an acute single acetaminophen overdose prevents hepatotoxicity in nearly all patients.
In this study, patients with normal serum alanine transaminase (ALT) and normal creatinine at presentation and at 12 hours along with acetaminophen level of <20 mg/L at 12 hours were assigned to either a 12 hour (250 mg/kg) or 20 hour (300 mg/kg) acetylcysteine (IV) infusion.
1411 Acetaminophen overdoses were identified; of these, 449 met criteria for study participation. 100 patients out of these 449 eligible were enrolled.
- There was no difference in ALT or INR at 20 hours between the two groups.
- No hepatotoxicity was evident in either group. 96 of 96 were well at 14-day telephone followup.
Discussion: “A normal ALT on presentation has a high negative predictive values (100%) of individuals developing any serious liver injury (ALT >1000 IU/L) in those receiving acetylcysteine.” [Al-Hourani et al. QJM 2013; 1065: 541-6)
My take: This study shows that a shortened acetylcysteine infusion is likely safe in selected patients at low risk for hepatotoxicity.
Related blog posts:
- Therapeutic Misadventures with Acetamiophen
- Predicting outcome in Pediatric Acute Liver Failure | gutsandgrowth
- N-acetylcysteine for Acute Liver Failure
- Advice on drug-induced liver injury (DILI) | gutsandgrowth
- When death is on the line | gutsandgrowth
- Pediatric pharmaceutical poisoning | gutsandgrowth
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition
A recent randomized study (Jeffrey B. Schwimmer, MD1,2; Patricia Ugalde-Nicalo, MD1; Jean A. Welsh, PhD, MPH, RN3,4,5; et al examined the beneficial effects of a low free sugar diet for Nonalcoholic Fatty Liver Disease (NAFLD) in adolescent boys. Congratulations to the authors, particularly to Miriam Vos (my Emory colleague & corresponding author) and Jeffrey Schwimmer (whose training overlapped with mine in Cincinnati).
“In this randomized clinical trial that included 40 adolescent boys aged 11 to 16 years with nonalcoholic fatty liver disease followed up for 8 weeks, provision of a diet low in free sugars compared with usual diet resulted in a greater reduction in hepatic steatosis [based on MRI] from 25% to 17% in the low free sugar diet group and from 21% to 20% in the usual diet group, a statistically significant difference of −6.23% when adjusted for baseline.”
Summary of this study in NY Times: To Fight Fatty Liver, Avoid Sugary Foods and Drinks
An excerpt from NY Times:
To make the diet easier and more practical for the children in the limited-sugar group to follow, the researchers asked their families to follow it as well. They tailored the diet to the needs of each household by examining the foods they consumed in a typical week and then swapping in lower sugar alternatives. If a family routinely ate yogurts, sauces, salad dressings and breads that contained added sugar, for example, then the researchers provided them with versions of those foods that did not have sugar added to them.
Fruit juices, soft drinks and other sweet drinks were forbidden. They were replaced with unsweetened iced teas, milk, water and other nonsugary beverages. Dietitians prepared and delivered meals to the families twice a week, which helped them stick to their programs.
Importance Pediatric guidelines for the management of nonalcoholic fatty liver disease (NAFLD) recommend a healthy diet as treatment. Reduction of sugary foods and beverages is a plausible but unproven treatment.
Objective To determine the effects of a diet low in free sugars (those sugars added to foods and beverages and occurring naturally in fruit juices) in adolescent boys with NAFLD.
Design, Setting, and Participants An open-label, 8-week randomized clinical trial of adolescent boys aged 11 to 16 years with histologically diagnosed NAFLD and evidence of active disease (hepatic steatosis >10% and alanine aminotransferase level ≥45 U/L) randomized 1:1 to an intervention diet group or usual diet group at 2 US academic clinical research centers from August 2015 to July 2017; final date of follow-up was September 2017.
Interventions The intervention diet consisted of individualized menu planning and provision of study meals for the entire household to restrict free sugar intake to less than 3% of daily calories for 8 weeks. Twice-weekly telephone calls assessed diet adherence. Usual diet participants consumed their regular diet.
Main Outcomes and Measures The primary outcome was change in hepatic steatosis estimated by magnetic resonance imaging proton density fat fraction measurement between baseline and 8 weeks. The minimal clinically important difference was assumed to be 4%. There were 12 secondary outcomes, including change in alanine aminotransferase level and diet adherence.
Results Forty adolescent boys were randomly assigned to either the intervention diet group or the usual diet group (20 per group; mean [SD] age, 13.0 [1.9] years; most were Hispanic [95%]) and all completed the trial. The mean decrease in hepatic steatosis from baseline to week 8 was significantly greater for the intervention diet group (25% to 17%) vs the usual diet group (21% to 20%) and the adjusted week 8 mean difference was −6.23% (95% CI, −9.45% to −3.02%; P < .001). Of the 12 prespecified secondary outcomes, 7 were null and 5 were statistically significant including alanine aminotransferase level and diet adherence. The geometric mean decrease in alanine aminotransferase level from baseline to 8 weeks was significantly greater for the intervention diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L) and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53 to 0.81 U/L; P < .001). Adherence to the diet was high in the intervention diet group (18 of 20 reported intake of <3% of calories from free sugar during the intervention). There were no adverse events related to participation in the study.
Conclusions and Relevance In this study of adolescent boys with NAFLD, 8 weeks of provision of a diet low in free sugar content compared with usual diet resulted in significant improvement in hepatic steatosis. However, these findings should be considered preliminary and further research is required to assess long-term and clinical outcomes.
Related blog posts:
- Fructose Resteriction Improved Fatty Liver Disease in Children
- Proof that Diet Changes Can Improve a Fatty Liver
- When Will MRI Obviate the Need for a Liver Biopsy in Pediatric NAFLD?
- Concise Review: Fatty Liver in Pediatrics
- Reaching Consensus on Bariatric Intervention in Children and Adolescents
- Fatty Liver Improved with Exercise
- Which Diet is Best For a Fatty Liver?
A recent study (S Feng, JC Bucuvalas, et al. Gastroenterol 2018; 155: 1838-51) found a high prevalence of chronic histologic injury even among highly selected long term liver transplant recipients with consistently normal liver biochemical tests. The authors were able to enroll 157 patients. In addition to histology, the authors examined gene expression/microarray transcriptional analysis, and immunohistochemical staining.
- Three clusters of patients were identified: interface activity (group 1, n=34), periportal/perivenular fibrosis without interface activity (group 2, n=45), and a group with neither (group 3, n=78).
- In this cohort, 96 (61%) had Ishak Fibrosis of Stage 0-1, 27 (17%) had Stage 2, 33 (21%) had Stage 3, and 1 (1%) had Stage 4-5.
- The authors identified a module of genes that regulate T-cell-mediated rejection that were associated with interface activity. Thus, interface activity in these patients connotes subclinical rejection, even in patients with consistently normal liver biochemistries.
What to do with this information:
“For patients whose biopsy samples harbor neither inflammation nor fibrosis, immunosuppression dose reduction may be reasonable…For patients, whose biopsy samples show fibrosis in the absence of inflammation, our data do not support any recommendations…for patients whose biopsy samples show interface hepatitis, our data indicate that dose reduction may be unwise. Although the intuitive response may be to escalate immunosuppression, data evidencing the benefit of this approach are lacking.”
My take: This study shows why a liver biopsy has been important prior to reducing immunosuppression (in liver transplantation and autoimmune hepatitis). My question is whether the authors could identify a gene signature/biomarker (like their gene module) that could be used as an alternative to a liver biopsy.
Related blog post:
Many times throughout the year we will receive a request to accept a 15-17 year old weighing more than 200 pounds with gallstones who needs to be transferred so that he/she can be cared for in a pediatric facility. The really crazy part is that some of these ‘kids’ need to transferred back to an adult facility to have an ERCP to remove the gallstones if they are lodged in the common bile duct (CBD). Very few pediatric gastroenterologists are adequately trained in ERCP.
A recent retrospective study (PC Bonasso et al JPGN 2019; 68: 64-7) shows some of the consequences of this problem –longer hospitalizations and delays in treatment. The authors compared 79 (48%) pediatric patients who required transfer compared to 85 (52%) who were managed at the tertiary care pediatric hospital. The median age was 15 years with 42% obese and 23% overweight.
- Transfer group patients had longer length of stay, median 7 days vs 5 days for non-transfer group (P< 0.0001) and more days between ERCP and surgery.
- Transfer patients were more likely to have an MRCP (34% vs 8% for non-transfer).
- Transfer patients were more likely to have a stent placement, 9% vs 5% (which would require a subsequent anesthetic to remove).
- Transfer patients were more likely to have a non-therapeutic ERCP; stone/sludge removal was 70% in transfer group vs 86% in non-transfer group. This could be related to the delay (eg. more time for stone to pass) or due to the evaluation by team not responsible for ERCP.
The authors note that there are fewer than 20 pediatric gastroenterologists trained in ERCP; this is not likely to change much in the near term due to the large number of ERCPs needed to become proficient and few options for pediatric training. Their study notes that 46% had adult gastroenterologist management for non-transfer group.
My take: This is clearly an area in need of collaboration. More pediatric hospitals need to have adult gastroenterologists available and adult hospitals need to consider keeping some of these young adults to improve both the care and costs for these individuals.
Related blog posts:
- How Good is Your ERCPist?
- Why an ERCP Study Matters to Pediatric Care
- What and When for ERCP with Gallstone Pancreatitis
Almost two years ago, the FDA approved Ledipasvir-Sofosbuvir (aka Harvoni) for pediatric patients 12-17 years of age with hepatitis C virus (HCV) infection. Now, a recent study (KF Murray, WF Balistreri, S Bansal et al. Hepatology 2018; 68: 2158-66) is likely to expedite approval for children ages 6-11 years of age.
In this open-label study with 92 patients, 88 had genotype 1, 89 received treatment with ledipasvir-sofosbuvir without ribavirin for 12 weeks, 97% were perinatally-infected, and 78% were treatment naive. The median age was 9 years. The dose (determined by intense pharmacokinetics) was 45 mg-200 mg (half the adult dosage). Two patients with genotype 3 HCV received ledipasvir-sofosbuvir for 24 weeks along with ribavirin.
- SVR12 was 99% (91/91). The single patient without SVR12 had relapsed 4 weeks after completing a 12 week treatment course.
- Ledipasvir-sofosbuvir was well-tolerated; the common adverse events reported were headache and pyrexia.
The authors note that while most children are considered to have mild symptoms or are asymptomatic, some progress to have significant fibrosis or cirrhosis, a small minority develop hepatocellular carcinoma, and HCV infection can impact both cognitive development and overall health.
My take: This study confirms that effectiveness of DAA therapy with ledipasvir/sofosbuvir in children as young as 6 years of age.
Related study: F Tucci et al. Hepatology 2018; 68: 2434-37. The authors report the successful treatment with ledipasvir/sofosbuvir of an infant with both SCID and HCV infection.
Related blog posts:
- New HCV Treatment Effective in Adolescents
- HCV Guidelines
- An “Ally” for Hep C Genotype 3
- A New Villain for Hepatitis C | gutsandgrowth
- Understanding HCV Treatment Failures with Sofusbuvir …
- Genotyping Still Matters for Hepatitis C (in 2018)
- Hepatitis C Infections Increasing Tied to Opioid Epidemic (in 2018)
- Opioid Epidemic Affecting Adolescent Hepatitis C Infections
- Heroin Epidemic Causing Surge in Hepatitis C Infections
- HCV now more deadly than HIV
- Hepatitis C : New and Newer Treatments
- Burden of Hepatitis B and Hepatitis C | gutsandgrowth
- Word of Caution with New Hepatitis C Medications | gutsandgrowth
Eradication of hepatitis C virus (HCV) is going to be difficult despite the huge improvements in treatment. One obstacle that has been highlighted previously has been the increase in HCV transmission associated with the opioid epidemic. Another basic problem is establishing a ‘cascade of care’ that makes sure that those with HCV receive appropriate treatment and followup.
In a recent study (RL Epstein et al. J Pediatr 2018; 203: 34-40, editoria by KB Schwarz, W Karnsakul 7-8) describe the deficiencies in the followup of women in an obstetric clinic serving women with substance use disorders. The authors reviewed electronic records of 879 women over a 10 year period. Key findings:
- 85% of women were screened for HCV. Of the 68% who were seropositive, only 72% had HCV RNA testing and 71% were viremic.
- There were 404 infants born to women who were HCVB seropositive. Only 45% of these infants completed AAP-recommended perinatal HCV screening.
In the commentary, the authors point to the suboptimal rates of followup. They note that there is a “huge gap between infected women and the linkage of their infected progency to care.” Furthermore, the AASLD has recommended that “all children with HCV infection in age groups for which direct-acting antiviral agents are approved should be treated.”
My take: this study identifies gaps in followup and treatment that need to be addressed systematically if we are to realize the goal of HCV eradication.
Related blog posts:
- Hepatitis C Cure: Too Late for Many | gutsandgrowth
- The Dark Cloud Inside the Silver Lining -What’s Really Going on with Hepatitis C Infection
- Increased organ availability due to opioid epidemic
- Opioid Epidemic –Devastating Impact on Children
- Hepatitis C Infections Increasing -Tied to Opioid Crisis
- Opioid Epidemic Affecting HCV Infection in Adolescents (as well as adults)