A recent study (P Kumar et al. JPGN 2018; 67: 75-9) examined suspected NAFLD in 12 to 18 year olds using data from NHANES. In the analysed cohort, there were 124 suspected NAFLD and 1385 without suspicion of NAFLD. This subset was weight to represent a U.S. population of over 18 million.
- Suspected NAFLD was defined by abnormal ALT (>25.8 U/L for boys and >22.1 U/L for girls) who did not have another explanation (eg. viral hepatitis, medication)
- Lean BMI was defined by BMI less than 85th% for age
- Hypertriglyceridemia ≥ 150
- Low HDL ≤ 40 mg/dL
- HOMA-IR =fasting glucose x insulin (microU/mL) divided by 405. Insulin resistance was defined as HOMA-IR ≥ 3
- Suspected NAFLD affects ~8% of lean adolescents in the U.S.
- Hypertriglyceridemia was noted in 10 of 124 suspected NAFLD and was a risk factor (P=0.028) as was Low HDL which occurred in 15 (P=0.016) and IR which occurred in 43 (P=0.053)
My take: Elevated ALT, a marker for fatty liver disease, is common even in adolescents without obesity. Elevated triglycerides, low HDL, and insulin resistance are all risk factors for suspected NAFLD in non-overweight/non-obese teens.
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Briefly noted: A small pilot study (n=9) (SS Sundaram et al. J Pediatr 2018; 198: 67-75) showed that treatment (with home CPAP) of obstructive sleep apnea (OSA) was associated with improved alanine aminotransferase levels, reduced metabolic syndrome markers and lower F(2)-isoprostanes (a marker of oxidative stress) in pediatric patients with nonalcoholic fatty liver disease (NAFLD). All nine of the participants were Hispanic males with a median age of 11.5 years; they had a median BMI of 29.5 and had biopsy-proven NAFLD. The improvement in NAFLD parameters occurred despite an increase in BMI. The authors note that studies in adults have shown contradictory findings with regard to whether treatment of OSA helps NAFLD.
My take: This study suggests potential beneficial liver effects of treating OSA. Regardless, treatment of OSA could be considered a quality metric in the care of children with NAFLD as better sleep at night has additional clear benefits.
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With nonalcoholic fatty liver disease (NAFLD), it is well-documented that adverse cardiovascular events influence mortality more than any other factor. Dyslipidemia plays an important role in these outcomes.
A recent study (KE Harlow et al. J Pediatr 2018; article in press. DOI: https://doi.org/10.1016/j.jpeds.2018.02.038) indicates that “clinically actionable dyslipidemia” is present in more than half of pediatric patients with NAFLD.
This multicenter, longitudinal cohort study included children (n=585) with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network.
- The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention
- Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention at baseline. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications.
My take: Assessing/managing dyslipidemia is an important component of NAFLD care.
Link to abstract: Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease
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C Sikavi et al. Hepatology 2018; 67: 847-57. This systematic review highlights that the combination of hepatitis C virus (HCV) infection and HIV infection is no longer a difficult-to-treat population with the implementation of direct-acting antivirals (DAAs). There are similar sustained virologic responses (SVRs) among those with and those without HIV. In clinical trials, patients with combined HCV-HIV had SVRs of 93.5-98% with DAA treatment; “real-world cohorts” had SVRs of 90.9%-98%.
MS Middleton et al. Hepatology 2018; 67: 858-72. Using data from the prospective CyNCh trial (cysteamine for NAFLD), the authors examined MRIs for diagnostic accuracy among 169 enrolled children. In this group, 110 (65%) and 83 (49%) had MRI and liver biopsy at baseline. MRI-PDFF (proton density fat fraction) was able to classify grade 1 steatosis from grade 2-3 steatosis with area under receiving operator characteristic curve of 0.87. Thus, this study shows MRI-estimated PDFF has high diagnostic accuracy.
G Mieli-Vergani et al. JPGN 2018; 66: 345-60. Position paper for Pediatric Autoimmune Liver Disease (AIH, ASC, de novo AIH after liver transplantation). This is a very useful review. A couple of pointers from the authors:
- “Present experience with budesonide as the first-line treatment is limited and does not appear to offer clear clinical advantage over the standard treatment”[prednisone]
- Fecal calprotectin should be obtained to evaluate for IBD in patients with autoimmune liver disease, “even in asymptomatic children.”
JM Cotter et al. JPGN 2018; 66: 227-33. This retrospective study with 39 patients with primary sclerosing cholangitis (PSC) showed a lack of correlation between liver tests and fibrosis at presentation. Average age of PSC diagnosis was 11.2 years, 74% had inflammatory bowel disease and 51% had autoimmune hepatitis. Related blog post: Big Pediatric PSC Study (with 781 children)
A recent prospective study (V Nobili et al. J Pediatr 2018; 194: 100-8) consecutively enrolled 20 severely obese adolescents with biopsy-proven nonalcoholic fatty liver disease (NAFLD). The authors used liver histology, immunohistochemistry and cytokine analysis to assess the changes (after 12 months) induced by bariatric surgery with laparoscopic sleeve gastrectomy (LSG).
- NAFLD Activity Score and fibrosis improved after LSG. Steatosis, hepatocyte ballooning, and NAS score showed a significant improvement (Z=-2.7; P=.007) at 12 months following surgery. Fibrosis improvement (Z=-2.449) was noted as well.
- The histologic improvement “is associated with activation of local cellular compartments (hepatic progenitor cells, hepatic stellate cells, and macrophages), thus, strengthening the role of cellular interactions and hepatic adipocytokine production in the pathogenesis of NAFLD.”
This study has a large number of figures illustrating the changes in liver architecture and immunohistochemistry changes.
My take: This study shows specific improvements following LSG and shows correlation with cytokines and immunohistochemistry providing a mechanistic explanation for these improvements.
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A recent guideline update (ZM Younossi. Liver Transplantation 2018; 24: 166-70) provides some useful information about nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver transplantation (LT).
- “Despite metabolic comorbidities, posttransplant outcomes of NASH patients are generally good. In fact, 1-, 3-, and 5-year patient and graft survival rates are …similar to other liver diseases.”
- NASH/NAFLD can recur following LT…”NASH with significant fibrosis (stage ≥2) occurs in approximately 5% of recipients by 5 years after transplantation.”
- Additional issues to manage after LT, include weight management, and metabolic conditions including diabetes, hypertension, dyslipidemia, and hypertension. All of these conditions can be affected by specific immunosuppressants. For example, calcineurin inhibitors and corticosteroids can exacerbate type 2 diabetes mellitus.
My take: This article indicates better LT outcomes than I expected in patients with NASH/NAFLD.
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Link: AASLD Guidance for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease
This guidance provides a 2018 review of NAFLD and current diagnostic/management recommendations in both adults and children. Some points from this practice guidance:
- “Liver-related mortality is the second or third cause of death among patients with NAFLD.” Cardiovascular disease remains the number one and cancer-related mortality is in the top three.
- “Routine screening for NAFLD in high-risk groups attending primary care, diabetes, or obesity clinics is not advised at this time because of uncertainties surrounding diagnostic tests and treatment options.” Likewise, screening of family members is not recommended.
- In children: “Because of a paucity of evidence, a formal recommendation cannot be made with regard to screening for NAFLD in children with overweight and obesity.”
- In patients undergoing evaluation with suspected NAFLD, the authors specifically recommend checking ferritin, iron saturation, and autoantibodies that could indicate autoimmune liver disease.
- In patients with suspected NAFLD, the authors recommend evaluation for comorbities including dyslipidemia, diabetes, hypothyroidism, polycystic ovary syndrome, and sleep apnea.
- “Liver biopsy should be considered in patients with NAFLD who are at increased risk of having…advanced fibrosis” and in “whom competing etiologies…cannot be excluded without a liver biopsy.”
- Pharmacologic therapies are not recommended in those without biospy-proven NASH and fibrosis. Specifically, the authors suggest consideration of pioglitazone and vitamin E and recommend against metformin, GLP-1 agonists, omega-3 fatty acids, and ursodeoxycholic acid.
- “Weight loss (7%-10%) is needed to improve the majority of histopathological features of NASH.”
- In patients with cirrhosis due to NASH, screening for varices is recommended and consideration of screening for HCC.
My take: This practice guidance is quite reasonable. At this time, more focus on systemic measures to counter overweight and obesity is crucial. Pharmacologic therapies for NAFLD will need to be effective for the cardiovascular, metabolic, and liver-related problems.
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