Improvement in Liver Fibrosis with DAA Treatment of Hepatitis C in Adolescents

A recent study showed improvements in measures of liver fibrosis at 12 months after treatment of Hepatitis C in Egyptian adolescents (DM Fahmy et al. J Pediatr 2021; 231: 110-116. Changes in Liver Stiffness and Noninvasive Fibrosis Scores in Egyptian Adolescents Successfully Treated with Ledipasvir-Sofosbuvir for Chronic Hepatitis C Virus Infection).

Methods: N=85. Liver stiffness measurement (LSM), by vibration-controlled transient elastography and noninvasive fibrosis scores (Firbosis-4, aspartate aminotransferase-platelet ratio index), were obtained before and 12 months after eradication with ledipasvir-sofosbuvir.

Key findings:

  • Overall, median baseline LSM was 5.8 (IQR, 4.2-6.5) and at follow-up 5.1 kPa (IQR, 4-6 kPa) (P = .045)
  • 16 patients (19%) experienced regression, and 46 (54%) nonprogression of LSM
  • The median baseline FIB-4 and aspartate aminotransferase-platelet ratio index scores were 0.34 (IQR, 0.22-0.47) and 0.35 (0.24-0.57), and at follow-up 0.3 (IQR, 0.22-0.34) and 0.2 (0.18-2.8) (P < .001, <.001), respectively

Limitations: In Egypt, HCV genotype 4 is predominant; thus, findings could be different with other HCV genotypes. In addition, the ‘gold’ standard in assessing fibrosis remains a liver biopsy.

In many liver conditions, effective therapy has been associated with histologic improvement/regression. So, while the findings in this study are expected, it is still nice to see more evidence of this outcome.

My take: This study supports the notion that elimination of HCV is associated with either regression or non-progression of liver fibrosis. Treatment prior to extensive liver damage is likely both effective and cost-effective.

Related blog posts:

Gibbs Gardens, 4/3/21

Neurologic Impairment with Biliary Atresia at Time of Diagnosis

Previous studies have indicated that prolonged cholestasis before liver transplantation is associated with adverse neurodevelopmental outcomes. LH Rodijk et al (JPGN 2021; 72: 592-596. Full text: Early Motor Repertoire in Infants With Biliary Atresia: A Nationwide Prospective Cohort Study) prospectively investigate early neurologic impairment in infants with biliary atresia (n=35).

The author’s utilized Prechtl’s General Movement (GM) Assessment which is a noninvasive, cost-effective, and worldwide used method to identify infants who are at risk of neurodevelopmental impairments. This requires video recordings of 10 minutes; this was avoided in the 24 hours following liver biopsy or general anesthesia.

Key finding:

  • The proportion of infants with atypical GMs was significantly higher in BA (46%) than in 2 reference groups of healthy infants (vs 10%, P < 0.001; vs 18%, P < 0.001).

My take (from authors): “At the time of diagnosis, almost half of the infants with BA showed an atypical early motor repertoire, suggesting that neurological impairment is present already in early infancy. Compared to healthy infants, approximately 2 to 3 times more infants showed an atypical motor repertoire.”

Related blog posts:

Arlington, VA -February 2021. Thanks to Seth for this image

Suboptimal Transitions: Pediatric to Adult Care

Two recent articles delve into the topic of Pediatric to Adult Care Transition.

M Katz et al. J Pediatr (Epub head of publication) 2021. African American Pediatric Liver Transplant Recipients Have an Increased Risk of Death After Transferring to Adult Healthcare (Thanks to a friend who shared this reference & congratulations to my Emory colleagues and senior author Nitika Gupta on this publication)

This retrospective study examined 101 patients between 1990 and 2015. 64 had long-term followup data available.

Key findings:

  • African Americans had higher rates of death after transfer than patients of other races (44% mor-
    tality vs 16%, representing 67% of all cases of death; P = .032)
  • 18 of the 64 (28%) died. Of those 18 deaths, 4 (22%) occurred within the first 2 years after transfer, and 10 (55%)
    within 5 years of transfer.
  • There was a high rate of medication nonadherence in patients who died. ” Death in our cohort was typically caused by chronic rejection and graft failure, with a high frequency of severe infections or bleeding events ultimately causing a patient to die.”
  • The average age of transplant in deceased patients was 15. Transplantation in teenage years could be a risk factor as well.
  • The authors note that “the years directly after transfer of care from pediatrics to adult medicine are high risk for death and poor patient outcomes. Racial disparities seen in pediatric medicine also hold true after transfer to adulthood.”

H Pearlstein et al. JPGN 2021; 72: 563-568. Predicting Suboptimal Transitions in Adolescents with Inflammatory Bowel Disease

This retrospective study with 104 subjects defined suboptimal transition as “either a return to pediatric care or requiring care escalation within 1 year of transfer.

Key findings:

  • 37 (36%) were determined to have a suboptimal transition.
  • Risk factors: mental health diagnosis (OR 4.15), medication non-adherence (OR 5.15), public insurance (OR 6.60), and higher Physician Global Assessment score at time of transition (OR 6.64).

Comments: This is a small study and included only 26 patients receiving public insurance, which the authors considered as a proxy measure of socioeconomic status.

My take: These studies show the difficulties and potential deadly outcomes that face these young adults during transition from pediatrics to adult care. In many cases, medication non-adherence is a key factor and can be affected by access to care, insurance coverage, and mental health. Most young adults with serious medical problems probably would benefit from keeping their parents actively involved in their care.

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March 30,2021. Washington D.C. Thanks to Seth for this picture.

Trends in Liver Diseases: Autoimmune Liver Diseases and Fatty Liver

1st Study: M Lamba et al. Clin Gastroenterol Hepatol 2021; 19: 573-579. Full text: Trends in Incidence of Autoimmune Liver Diseases and Increasing Incidence of Autoimmune Hepatitis

This was a population-based prospective study from Canterbury, New Zealand

Key findings:

  • Overall incidence rates were 1.93 per 100,000 for AIH (95% CI, 1.58–2.34), 0.51 per 100,000 for PBC (95% CI, 0.33–0.73), and 0.92 per 100,000 for PSC (95% CI, 0.68–1.21). 
  •  The incidence rate of AIH was significantly higher during the period of 2014–2016 (2.39 per 100,000; 95% CI, 1.76–3.23) than during the period of 2008–2010 (1.37 per 100,000; 95% CI, 0.91– 2.06) (P < .05). Incidences of PBC and PSC did not change significantly.
  • In 2016, prevalence values were 27.4 per 100,000 for AIH (95% CI, 23.58–32.0), 9.33 per 100,000 for PBC (95% CI, 7.13–12.05), and 13.17 per 100,000 for PSC (95% CI, 10.56–16.42).

My take: This study indicates that autoimmune hepatitis has been increasing in incidence.

Related blog posts:

2ndStudy: ZM Younossi et al. Clin Gastroenterol Hepatol 2021; 19: 580-589. Full text: Nonalcoholic Steatohepatitis Is the Most Rapidly Increasing Indication for Liver Transplantation in the United States

This study was an analysis of data from the Scientific Registry of Transplant Recipients (2002 through 2019).

Key findings:

  • In 2002, the most common etiologies of non-acute liver failure on the liver transplant waitlist (in patients without HCC)
  • In 2019, among patients without HCC, NASH was the second leading indication for liver transplantation (28% of patients), after ALD (38% of patients). were chronic HCV infection (37%) and ALD (16%), whereas only 5% had NASH
  • HCC accounted for 27,799 patients (16.5%) and was commonly due to chronic HCV throughout study period

My take: Demand for liver transplantation has NOT improved despite curative therapy for chronic hepatitis C. This is due to increased liver failure related to fatty liver disease and alcoholic liver disease.

Related blog posts:

Figure 1 Prevalence of the most common CLD etiologies in waitlisted liver transplant candidates without HCC. (A) Proportion of all non-HCC listings with known etiology; (B) the proportion relative to that seen in 2002.

Juice in Infancy and Fatty Liver Disease

Briefly noted: ML Geurtsen et al. Hepatology 2021; 73: 560-570. Full text: Associations Between Intake of Sugar‐Containing Beverages in Infancy With Liver Fat Accumulation at School Age

Methods: In a population‐based prospective cohort study of 1,940 infants, we assessed sugar‐containing beverage intake (juice or soda) at 1 year with a validated Food Frequency Questionnaire. Liver fat fraction and NAFLD (liver fat fraction ≥5.0%) were assessed with MR. Key findings:

  • Compared to infants with <1.0 serving/day, those with >2.0 servings/day had the highest odds of NAFLD at 10 years of age (OR, 3.02; 95% CI, 1.34, 6.83). This was independent of sugar‐containing beverage intake and body mass index at school age
  • Liver fat fraction greater than or equal to 5% in school-aged children was almost 3-fold higher in those who consumed more than two servings of juice per day at age 1 (4.0%) than in those who drank less than one per day (1.4%)
  • The associations between juice intake in infancy and NAFLD were strongest in children with overweight or obesity at age 10 and those in families with more limited education

Major strengths of this study are the population‐based prospective longitudinal design with a large sample size, with information on sugar‐containing beverage intake in infancy and liver fat fraction measured with MR at 10 years of age.

My take: Juice and other high sugar beverages (eg soda) should be avoided, particularly at younger ages.

Related blog posts:

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The Best Time To Treat Children with Hepatitis C And Cost Considerations

E Greenaway et al. J Pediatr 2021; 230: 38-45. Treatment of Chronic Hepatitis C in Young Children Reduces Adverse Outcomes and Is Cost-Effective Compared with Deferring Treatment to Adulthood

Related editorial: N Rodriguez-Baez. J Pediatr 2021; 230: 9-10. Full text: Hepatitis C in Young Children: To Treat or Not to Treat – Is It Cost-Effective?

In this study, the authors used a state-transition model to assess cost-effectiveness of hepatitis C virus (HCV) infection in children; the model treated a hypothetical cohort of 10,000 children with chronic HCV at age 6 years with combination therapy of sofosbuvir/ledipasvir for 12 weeks vs deferring treatment until 18 years of age.

Key findings:

  • The incremental cost effectiveness of early treatment of young children was $12 690 per QALY gained after 20 years, which is considered cost effective compared with deferred treatment.
  • The authors note that if the cost of DAA medications dropped by 60%, then early treatment would not be more cost effective.
  • However, early treatment of 10,000 children would prevent 330 cases of cirrhosis, 18 cases of hepatocellular carcinoma, and 48 liver-related deaths.
  • The investigators presented an additional scenario treating children as young as 3 years of age and using alternative treatment with the pan-genotypic combination of glecaprevir/pibrentasvir for 8 weeks; using glecaprevir/pibrentasvir resulted in an incremental cost effectiveness of $12 563 per QALY compared with deferring treatment to age 18 years.

All cost effective models have built in assumptions. This model, for example, presumes each patient is offered treatment only once and does not get reinfected before age 18 years.

Other aspects about early treatment that are difficult to quantitate:

  • Improved adherence at younger age which improves cost effectiveness
  • Reduction in transmission of HCV as a consequence of successful treatment
  • Detrimental effects of untreated/deferred treatment HCV on quality of life, psychosocial health, and cognitive functioning

My take: This study (& editorial) demonstrate that early treatment of HCV is a good value and delivers non-economic benefits as well. Every child (>3 years) with HCV should be treated and cured of HCV infection.

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From Journal of Pediatrics twitter feed

Liver Shorts: Delisting Transplant Candidates, Albumin Infusions for Cirrhosis, Terlipresin & Liver Learning System

KL Karunungan et al. Liver Transplantation 20021: 27: 200-208. Impact of Payer Status on Delisting Among Liver Transplant Candidates in the United States

This was a retrospective study which relied on large national databases.

  • The 1‐year cumulative incidence of delisting was 9.0% (95% confidence interval [CI], 8.3%‐9.8%) for patients with private insurance, 10.7% (95% CI, 9.9%‐11.6%) for Medicare, and 10.7% (95% CI, 9.8%‐11.6%) for Medicaid
  • Medicare (HR, 1.20; 95% CI, 1.17‐1.24; P < 0.001) and Medicaid (HR, 1.20; 95% CI, 1.16‐1.24; P < 0.001) were independently associated with an increased hazard of death or deterioration compared with private insurance.
  • The article highlights regional variation in payor coverage and change in watilist death or deterioration from 2002-2018 (Figure 1)
  • Higher levels of education and employment were protective against waitlist mortality and deterioration
  • Female sex was a risk factor for delisting which may be in part to body size as women are more likely to have an organ declined as a result of small stature

L China et al. NEJM 2021; 384: 808-17. A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis This was the ATTIRE trial; somehow ATTIRE is an acronym to allude to “Albumin to Prevent Infection in Chronic Liver Failure.” This trial was a multicenter, randomized controlled study.

“In patients hospitalized with decompensated cirrhosis, [daily] albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care.” The standard of care included giving albumin under specific circumstances: large volume paracentesis, spontaneous bacterial peritonitis, or hepatorenal syndrome. Infusions (20% albumin) were infused at a rate of 100 mL/hr. In addition, the albumin group, which received 10 times as much albumin as the standard group, had more severe or life-threatening adverse events, especially pulmonary edema or fluid overload.

F Wong et al. NEJM 2021; 384: 818-828. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome In this multicenter, randomized controlled study, terlipressin was associated with improved renal function -reversal of HRS occurred in 32% compared to 17% in placebo group; however, it was associated with increased serious adverse events (eg. respiratory failure) and increased death (51% vs 45% in placebo group).

ER Perito et al. JPGN 2021; 72: 417-424. A Learning Health System for Pediatric Liver Transplant: The Starzl Network for Excellence in Pediatric Transplantation The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) is the first multicenter effort by pediatric liver transplant teams. Its goal is to establish and share evidence-based care to improve liver transplantation outcomes. If successful, SNEPT should be to liver transplantation as ImproveCareNow network is for pediatric inflammatory bowel disease.

Is Fatty Liver Increased in Pediatric Population with Type 1 Diabetes Mellitus?

J Sae-wong et al. J Pediatr 2021; 230: 32-37. The Prevalence of Nonalcoholic Fatty Liver Disease and Its Risk Factors in Children and Young Adults with Type 1 Diabetes Mellitus

In this cross-sectional study with 50 children with Type 1 Diabetes Mellitus (T1DM), MRE and MRI-PDFF studies were undertaken to determine whether the participants had nonalcoholic fatty liver disease (NAFLD). Key findings:

  • The median age and duration of T1D were 16.9 years (IQR, 13.6-20 years) and 6.5 years (IQR, 4-11 years), respectively. 26% of the cohort were overweight or obese.
  • The prevalence of NAFLD was 10% (more than half had normal ALT values). Four out of 5 patients with NAFLD were overweight/obese, and 2 had an and elevated alanine aminotransferase (ALT) level. None had liver fibrosis (defined as MRE >2.9 kPa).
  • High BMI-SDS (body mass index standard deviation score) was the sole independent risk factor associated with NAFLD (OR, 5.79; 95% CI, 1.04-32.18).

My take: This study is reassuring regarding the prevalence of NAFLD in children and young adults with T1D which was comparable to that in the general population. Routine screening for NAFLD in patients with T1D does not appear to be useful.

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Liver Shorts -March 2021. Neonatal liver disease, Hepatitis-Associated Aplastic Anemia & Two

S Kemme et al. JPGN 2021; 72: 194-201. Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series This small case series (n=4) with HAAA found that this condition was poorly responsive to steroids, azathioprine and tacrolimus; however, Anti-Thymocyte Globulin (ATG) was associated with sustained biochemical remission of the hepatitis. Two patients underwent hematopoietic stem cell transplantation. All patients had extensive investigations. All had evidence of systemic hyperinflammation (with markedly-elevated ferritin and soluble IL-2 R levels) and CD8+ T cell predominant liver tissue infiltration.

C Potter. JPGN Reports 2021; 1: e031. doi: 10.1097/PG9.0000000000000031. Full text: The Role of a NICU Hepatology Consult Service in Assessing Liver Dysfunction in the Premature Infant This was a retrospective observational study of 157 consecutive babies were evaluated by a single hepatologist. The approach outlined by this study:

  1. Workup: In the well and stable premature with elevated DB, “aminotransferases, AP, GGT, glucose, T4, TSH, UC, urine CMV PCR, and US with Doppler evaluation should be obtained…Coagulation studies in well babies with other evidence of good synthetic function are not necessary.” Empiric ursodeoxycholic acid may be given with weekly evaluation.
  2. Genetic testing: “Genetic panels are indicated in babies with no obvious risk factors after the first tier of studies…In critically ill babies with multisystem disease, critical whole exome sequencing (WES) is faster and provides broader results.”
  3. Sepsis: Babies with sudden increase in DB and ALT should be evaluated for sepsis (including urosepsis) and CMV.
  4. Nutritional support: Infants should be “supported with MCT and vitamin supplementation.”
  5. Severe liver disease: “Babies with coagulopathy and marked elevation of aminotransferases who have multiorgan failure in the first few days of life need to be evaluated for perinatal complications, severe metabolic disease, and gestational alloimmune liver disease (GALD). In this period, ischemic shock or infectious disease is much more common than primary liver disease, but the presentations can overlap.”
  6. Liver biopsy: “Liver biopsy should be pursued in babies whose cholestasis is not improving and the diagnosis is unclear.”
  7. Etiology: Infection, genetic disease, cardiac dysfunction, large heme loads, and hypothyroidism are common causes of liver dysfunction in the NICU. Common findings included trisomy 21-associated liver dysfunction (n=12), and thyroid disease. 6 patients had type 2 Abenathy shunts -only one required closure. Two patients had biliary atresia. Other liver diseases identified included GALD (n=2), PFIC2, Alagille, Alpha-one-antitrypsin, Cystic Fibrosis, and Niemann-Pick.

Related blog posts:

Wahid N et al. AASLD 2020, Abstract 153. Summary from GI & Hepatology News: Liver-related deaths decline after Medicaid-expansion under ACA. “Beginning around 2015, liver-related deaths began to decline in expansion states by a mean of –0.6%, while they continued on an upward trajectory in the nonexpansion states…“It’s a no-brainer that the lack of insurance accessibility for the most vulnerable people in the United States meant that they were dying of cirrhosis instead of being transplanted,” said Elliot Benjamin Tapper, MD, of the University of Michigan, Ann Arbor.”

W-M Choi et al. Clin Gastroenterol Hepatol 2021; 19: 246-258. Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection: A Systematic Review and Meta-analysis “In a meta-analysis of studies of patients with chronic HBV infection, we found that TDF treatment was associated with a significantly lower (20%) risk of HCC than entecavir treatment. Randomized trials are needed to support this finding.” This analysis comprised 15 studies (61,787 patients; 16,101 patients given TDF and 45,686 given entecavir).

Related blog posts:

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Success of Isolated Heart Transplantation in the Setting of Fontan-Associated Liver Disease & How COVID Vaccines Work

A small retrospective analysis by my Emory colleagues (DS Rodriguez et al [Senior author R Romero]. J Pediatr 2021; 229: 78-85. Pretransplantation and Post-Transplantation Liver Disease Assessment in Adolescents Undergoing Isolated Heart Transplantation for Fontan Failure) examines outcomes of 9 patients with Fontan-associated liver disease (FALD) who underwent liver transplantation.

All of these patients underwent extensive evaluations. Key findings:

  • Central venous pressures and VAST scores decreased significantly post-transplantation
  • Fontan liver MRI score maximum was 10 pretransplantation and decreased significantly post-transplantation
  • Pretransplantation and post-transplantation liver biopsy scores did not differ in 4 paired biopsy specimens
  • Patients with FALD and MELD <15, MELD-XI <16 (MELD XI excludes INR), Fontan liver MRI score <10, and VAST (varices, ascites, splenomegaly, thrombocytopenia) score ≤2 can have successful short-term isolated heart transplantation outcomes

My take: This study provides reassurance that heart transplantation can proceed in patients with FALD, which is helpful as hepatic fibrosis is nearly universal in this population. After transplantation, surveillance is still needed for hepatic complications including hepatocellular carcinoma.

Related blog posts:

From Eric Topol’s Twitter Feed