How Often Does a Fatty Liver Start in Infancy?

K McNelis et al. JPGN Reports; 2021: 2(3):e113. Open Access: Hepatic Steatosis in Infancy: The Beginning of Pediatric Nonalcoholic Fatty Liver Disease?

In this retrospective study of 65 healthy infants (<3 months of age, median age 2 months) who had CT scans performed due to trauma, the authors investigated the frequency of a fatty liver.

Key findings:

  • Depending on the criteria used, 23% or 26% of infants had evidence of fatty liver on CT scan
  • The prevalence of maternal obesity and/or diabetes was 11% (of the 65 pregnancies) but there was no significant difference in maternal risk factors between infants with and without evidence of steatosis

My take: Whether the fatty liver seen on CT scans in this infant cohort persists and evolves to adolescent and adult fatty liver disease is unknown but intriguing.

Hepatic Steatosis as an Incidental Finding

A recent report (H Okura et al. J Pediatr 2021; 234: 92-98. Under-reporting of Hepatic Steatosis in Children: A Missed Opportunity for Early Detection) showed that hepatic steatosis is under-reported as an incidental finding on CT scans which were ordered for nephrolithiasis.

Key findings:

  • Using absolute liver attenuation <48 Hounsfield units (HU), the prevalence was 7% (n = 42/584). Steatosis was reported for only 12 of 42 (28%) of these patients and was documented in clinical notes in only 3 of those cases
  • 232 (40%) had liver enzymes available within 24 hrs of CT scan. 79 had elevated ALT values; steatosis accounted for only 22% of those with elevated ALT values
  • In those with liver attenuation < 48 HU, nearly all had abnormal ALT values and the median was 52 U/L
  • Patients with steatosis had an 8-fold likelihood of overweight/obesity

Discussion:

  • These findings are similar to an adult study of 1290 patients in which 26% had steatosis but only 5% had those findings identified and documented beyond the radiology report. (N Kutaiba et al. J Med Imaging Radiat Oncol 2019; 3: 431-8)
  • CT findings are considered much more accurate than ultrasonography.
  • The authors argue that identification of NAFLD is “crucial” to allow for further specialty evaluation and to exclude secondary causes of steatosis.

My take: This study shows that there is an opportunity to improve identification of incidental steatosis. If identified, this can/should be addressed by their primary care team to emphasize improved diet choices and physical activity.

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From Journal of Pediatrics Twitter Feed

Increased Cancers with Fatty Liver Disease

Z Wang et al. Clin Gastroenterol Hepatol 2021; 19: 788-796. Associations Between Nonalcoholic Fatty Liver Disease and Cancers in a Large Cohort in China

It is well-recognized that obesity/overweight increases the risk of cancer (related blog post: Cancer due to Overweight/Obesity). Wang et al provide data regarding cancer risk due specifically to nonalcoholic fatty liver disease (NAFLD) from a large prospective adult cohort (n=54,187). Key findings:

  • Prevalence of NAFLD, based on ultrasonography, was 32.3%.
  • NAFLD was associated with increased risk of all cancers (hazard ratio [HR], 1.22; 95% CI, 1.10–1.36; P = .0001), thyroid cancer (HR, 2.79; 95% CI, 1.25–6.21; P = .01), and lung cancer (HR, 1.23; 95% CI, 1.02–1.49; P = .03).
  • Increased risk for colorectal cancer (HR, 1.96) and lung cancer (HR, 1.38) was demonstrated only in smokers.  An association between NAFLD and kidney cancer (HR, 1.57; 95% CI, 1.03–2.40) was only observed in men without diabetes.
  • Risk of hepatocellular carcinoma was increased only in those with elevated ALT values of 80 U/L or more (HR 8.08)

My take: This study shows that NAFLD increases the risk of cancer; much of this risk may be due to obesity/metabolic syndrome and associated chronic inflammation. Overall, cardiovascular disease in patients with NAFLD represents a higher risk for morbidity and mortality.

Related blog posts:

Peonies

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.

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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Best Practice for Fatty Liver Disease

ZM younossi, KE Corey, JK Lim. Gastroenerol 2021; 160; 912-918. AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review

Some of the Best Practice Advice Recommendations:

  • #1 “Lifestyle modification using diet and exercise to achieve weight loss is beneficial for all patients with nonalcoholic liver disease (NAFLD).”
  • #2 Weight loss leads to improvement. >5% wt loss can decrease steatosis, >7% can lead to resolution of NAFLD, >10% can stabilize or reduce fibrosis
  • #3 “Adults with NAFLD should follow the Mediterranean diet…as well as limit or eliminate consumption of commercially produced fructose”
  • #8 Evaluate for coexisting conditions, such as “obesity, diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease.”

Also another publication on fatty liver disease:

LF Chun et al. J Pediatr 2021: https://doi.org/10.1016/j.jpeds.2021.01.064. Hepatic Steatosis is Negatively Associated with Bone Mineral Density in Children

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Liver Shorts -February 2021 (part 1)

T Mayr et al. JPGN 2021; 72: 115-122. Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?

In this retrospective study with 31 children with Wilson’s disease (most of whom had had previous penicillamine), those who received more than 20 mg/kg/day of trientine therapy had increased adverse effects compared to those who received less than 20 mg/kg/day: 63% vs 7%; median followup was 60 months. In addition, there was not increased response to higher doses. The authors note that trientine had lower incidence of adverse effects compared to penicillamine and “appears to be the preferred” as a first-line treatment.

J Teckman et al. (ChiLDReN Network). J Pediatr 2020; 227: 81-86. Longitudinal Outcomes in Young Patients with Alpha-1-Antitrypsin Deficiency with Native Liver Reveal that Neonatal Cholestasis is a Poor Predictor of Future Portal Hypertension

In this prospective cohort with 350 participants (all with either PiZZ (90%) or PiSZ (10%) and native livers), 278 (79%) entered the cohort (in 2007 or later) without portal hypertension and 18 developed portal hypertension during follow-up. Portal hypertension was defined by development of ascites, varices or combination of splenomegaly/thrombocytopenia. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. Median length of followup was 2.5 years. My take: While most children with Alpha-1-Antitrypsin Deficiency do well, monitoring is warranted as some will develop progressive liver disease (even in the absence of neonatal cholestasis).

SA Harrison et al. Gastroenterol 2021: 160: 219-231. Full text PDF: Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis

In this phase 2 double-blind study with 78 patients with NASH, at week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%) (P=.002). Fibrosis improvement (1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of
patients receiving placebo (P = .10). And, NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20)

A Chanpong, A Dhawan. JPGN; 2021: 72: 210-215. Long-Term Urinary Copper Excretion on Chelation Therapy in Children with Wilson Disease Key finding:  24-hour UCE decreases to ≤8 μmol/day and <6 μmol/day after 1 and 5 years of treatment, respectively.

Related blog posts:

Surprise, Surprise: Inadequate Physical Activity is a Predictor of Fatty Liver Disease (Plus 2)

Briefly noted:

Hepatology 2020; 72: 1556-1568. Inadequate Physical Activity and Sedentary Behavior Are Independent Predictors of Nonalcoholic Fatty Liver Disease. D Kim et al found that leisure‐time physical activity (≥150 minutes per week) demonstrated 40% lower odds of NAFLD. This study used the 2007‐2016 US National Health and Nutrition Examination Survey with 24,588 participants; the authors defined NAFLD based on three noninvasive panels.

Liver Transplantation 2020; 26: 1409-1421. Low Health Literacy Is Associated With Frailty and Reduced Likelihood of Liver Transplant Listing: A Prospective Cohort Study. T Bittermann et al showed that low health literacy was independently associated with physical frailty (adjusted odds ratio [aOR], 3.59; 95% confidence interval [CI], 1.50‐8.59; P = 0.004) and not being wait‐listed (aOR 1.96; 95% CI, 1.03‐3.75; P = 0.04).

Liver Transplantation 2020; 26: 1477-1491. Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis. In this retrospective study with 87 patients who underwent liver transplantation for PSC, 52 (60%) had pre-existing IBD. Key findings:

  • Excluding those who died within the first 3 months, the 10‐year patient survival and graft survival rates were 92.6% and 77.1%, respectively, in the PSC with IBD (PSC‐IBD) group and 97.1% and 83.2% in the isolated PSC group, respectively.
  • The rate of recurrent PSC was 21% in the PSC‐IBD group and 11% in the isolated PSC group

Thus, it appears that having pre-existing IBD did not significantly influence survival after transplantation.

Genetic Testing for Fatty Liver Disease Is Not Ready For Routine Use

A recent study (H Gellert-Kristensen et al. Hepatology 2020; 72: 845-856. Combined Effect of PNPLA3TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population) describes genetic risk score (GRS) which can stratify the risk of developing cirrhosis and hepatocellular carcinoma.

The study utilized data and plasma markers from 110,761 individuals from Copenhagen, Denmark, and 334,691 individuals from the UK Biobank. GRS scores were from 0 to 6 based on three common genetic variants: PNPLA3, TM6SF2, and HSD17B13.

Key finding:

  • A GRS of 5 or 6 (compared to GRS of 0) for fatty liver disease confers up to a 12‐fold higher risk of cirrhosis and up to a 29‐fold higher risk of HCC in individuals from the general population

The editorial by RM Pfeiffer et al (Hepatology 2020; 72: 794-795. Genetic Determinants of Cirrhosis and Hepatocellular Carcinoma Due to Fatty Liver Disease: What’s the Score?) is very helpful in placing the findings in context.

  • Only 0.5% of individuals had a GRS of 5 or 6. “A GRS of 4 [or more] which still conveyed large risks (cirrhosis, OR =5.2; HCC, OR =3.3) was found in approximately 5% of this population.”
  • Using a GRS of 4 or more, the positive predictive value of GRS-based test in the Danish population is “0.008 for cirrhosis and 0.003 for HCC. In other words, among 1000 persons with GRS greater than or equal to 4, only 8 will develop cirrhosis and 3 will develop HCC.”

My take: This study confirms that specific genetic variants increase the risk of complications from fatty liver disease. However, poor predictive value will likely preclude routine application.

ACG Review (Zobair Younassi, MD): NAFLD and NASH

For PDF copy of slides: NAFLD and NASH

Dr. Zobair Younassi gave a recent virtual grand rounds –here are some of the slides:

Epidemiology:

Natural History:

  • Progression of disease is not linear
  • Fatty liver disease is a multisystem disorder.  Cardiovascular disease is leading cause of death in patients with fatty liver disease
  • Fatigue (~50%) is common with fatty liver disease

Main treatment:

  • Weight loss -Mediterranean diet may be helpful
  • Exercise
  • No FDA-approved treatments, though pioglitizone supported by AASLD for biopsy-proven NASH
  • Public health interventions are needed