Type 2 Diabetes in Children with Nonalcoholic Fatty Liver Disease

JB Schwimmer et al. Clin Gastroenterol Hepatol 2022; DOI:https://doi.org/10.1016/j.cgh.2022.05.028. Pre-proof full text PDF:Incidence of Type 2 Diabetes in Children with Nonalcoholic Fatty Liver Disease

Methods: Children with NAFLD (n=892) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network were followed longitudinally. These children had a mean age of 12.8 years followed for a mean of 3.8 years 

Key findings:

  • At baseline, 63 (of 892) children had T2D, and during follow-up, an additional 97 children developed incident T2D, resulting in a period prevalence of 16.8 %.
  • Incident T2D was significantly higher in females versus males (HR 1.8 [1.0-2.8]), associated with BMI z-score (HR 1.8), and more severe liver histology including steatosis grade (HR 1.3), and fibrosis stage (HR 1.3).

My take: Children/adolescents with NAFLD need to be monitored for the development of T2D.

Related blog posts:

Thanks to David for picture of Portland Head Lighthouse

Sugary Beverage and Liver Stiffness in Healthy Adults

CW Leung, EB Tapper. Clin Gastroenterol Hepatol 2022; 20; 959-961. Sugar-sweetened Beverages Are Associated With Increased Liver Stiffness and Steatosis Among Apparently Healthy Adults in the United States

In this representative sample (2706 adults, median 37.9 years) from 2017-2018 NHANES, subjects without any known chronic disease had tow 24-hr dietary recalls collected and had liver stiffness measurements (LSM) and controlled attenuation parameters (CAP); LSM <7 kPa (using vibration-controlled transient elastography) was considered low risk for advanced fibrosis and CAP >248 dB/m were at risk for heaptosteatosis. Key findings:

  • 11% (n=305) had LSM >7.0 kPa and 46% (n=1254) had CAP >248 dB/m
  • Sugar-sweetened beverage (SSB) >2/day was associated with greater LSM (OR 2.30)
  • In mutlivariate analysis, consuming >1-2 sugar-sweetened servings per day was associated with elevated CAP (OR 1.51 compared to adults with SSB consumption
  • Limitations: this cross-sectional study cannot prove causality

My take: Even in healthy adults, SSB consumption is associated with detrimental changes in the liver.

Related blog posts:

Liver Shorts: Biliary Atresia Organoids, AIH Pregnancy Outcomes, ALT Levels in Primary Care, Polyreactive IgG for AIH

SP Amarachintha et al. Hepatology 2022; 75: 89-103. Open Access: Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia

This is a super cool article documenting a new human model for studying biliary atresia. The authors “generated biliary organoids from liver biopsies of infants with biliary atresia and normal and diseased controls…Organoids from biliary atresia are viable and have evidence of halted epithelial development. The induction of developmental markers, improved cell-cell junction, and decreased epithelial permeability by EGF and FGF2 identifies potential strategies to promote epithelial maturation and function.”

The authors note that delayed development of cholangiocytes impair barrier function and leave the liver susceptible to various insults which can trigger an inflammatory response with potential progression to obliteration of the bile ducts.

CW Wang et al. Hepatology 2022; 75: 5-12. Open Access: Outcomes of pregnancy in autoimmune hepatitis: A population-based study

Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Key findings:

  • AIH was not associated with postpartum hemorrhage, maternal, or perinatal death
  • AIH was associated with preterm births when compared with women without CLD (OR: 2.0)
  • The odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2 and hypertensive complications: OR: 1.8) and also compared to no CLD in pregnancy (GDM: OR: 2.4 and  hypertensive complications: OR: 2.4)

SJ Wu et al. J Pediatr 2022; 240: 280-283. The Prevalence of Elevated Alanine Aminotransferase Levels Meeting Clinical Action Thresholds in Children with Obesity in Primary Care Practice

In this brief report, the authors identified 7.8% of children from a cross-sectional California cohort (n=12,945) with ALT >44 U/L and BMI in the 95% or higher (2012-2014). Males were twice as likely to have elevated ALT. Ethnicity rates were higher in hispanics, asians than white and black children (in males: 12%, 10.4%, 7.3% and 3.1%, respectively)

R Taubert et al. Hepatology 2022; 75: 13-27. Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis

Key findings: Polyreactive IgGs (pIgGs) are a common finding in untreated AIH and have “the highest overall accuracy for the distinction between AIH and non-AIH LD compared to the most common conventional autoantibodies.” In addition, in this study with 1568 adutls, pIgGs were present in “up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD.”

Autoantibodies Significance in Pediatric Fatty Liver Disease

A Khayat, B Vitola et al. J Pediatr 2021; 239: 155-160. Prevalence and Clinical Significance of Autoantibodies in Children with Overweight and Obesity with Nonalcoholic Fatty Liver Disease

When investigating elevated liver enzymes in teenagers, serology for autoimmune hepatitis (AIH) is frequently obtained. In the face of overweight/obesity, the majority will have nonalcoholic fatty liver disease (NAFL). How many with elevated autoantibodies actually have autoimmune liver disease (ALD)? Some information regarding this issue is available in the article by Khayat et al.

Methods: A retrospective, cross-sectional study of 181 children with a biopsy-proven diagnosis of NAFL, NASH, autoimmune hepatitis (AIH), or primary sclerosing cholangitis (PSC) and a body mass index (BMI) >85th percentile treated between 2007 and 2016.

Key findings:

  • Antinuclear antibody (ANA), anti-actin antibody, and anti–liver kidney microsomal (LKM) antibody were positive in 16.1%, 13.8%, and 0%, respectively, of the patients with NAFL and in 32.8%, 15.5%, and 0%, respectively, of those with NASH
  • Total immunoglobulin G (IgG) was elevated in 27.3% of the patients with NAFL and in 47.7% of those with NASH, but in 100% of those with ALD. A normal IgG level was the “strongest negative predictor of ALD, followed by a negative ANA and actin.”
  • The positive predictive value of LKM was 100% for ALD but only 29% for ANA and 46% for anti-actin antibody. ANA positivity in this cohort was associated with more insulin resistance
  • ALD was present in 29/181 (16%).  12 (6.6%) with isolated ALD (AIH, PSC, or overlap), and 17 (9.4%) with combined ALD and NAFLD
  • BMI >98% “appears to be an important breakpoint above which ALD is less likely” even when IgG is high with a positive ANA
  • Limitations: Retrospective study, not every patient had all of the ALD serology tests

My take: Even heavy kids may have autoimmune liver disease. In those with abnormal serology, about 1 in 6 will have ALD, either in combination with NAFL or as the sole etiology of abnormal LFTs.

Related blog posts:

Liver Shorts: Autoimmune Liver Disease/HLA profiles, Saroglitazar for fatty liver, and Liver Transplantation Survivorship

Y Ma et al. Hepatology 2021; 74: 2032-2046. Open Access: Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry

The main reason I had to highlight this article is the study period was 42 years!!! (1977-2019, n=236 children). Key findings: “Unique HLA profiles are seen in each subgroup of juvenile AILD:  DRB1*03 for AIH-1, DRB1*03 plus DRB1*07 for AIH-2, and DRB1*13 for ASC. DRB1*03 and the A1-B8-DR3 haplotype are disease-predisposing genes for all three subgroups. The influence of HLA class II genes on disease severity is strong, DRB1*03 homozygosity and possession of DRB1*13 being associated to histologically more advanced disease from onset, while DRB1*07 is linked to the least optimal response to immunosuppression”

S Gawrieh et al. Hepatology 2021; 74 1809-1824. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial

The “EVIDENCES IV study was a multicenter, randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of saroglitazar.” n=106. Key findings:

  • For ALT: mean percent change from baseline at week 16 was −25.5% (5.8), −27.7% (5.9), and −45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all)
  • Compared with placebo, saroglitazar 4 mg improved liver fat content on MRI PDFF (4.1% [5.9] vs. −19.7% [5.6]), adiponectin (−0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment–insulin resistance (−1.3 [1.8] vs. −6.3 [1.7]), and triglycerides (−5.3 mg/dL [10.7] vs. −68.7 mg/dL [10.3]) (P < 0.05 for all)
  • Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27)

My take: This study shows the potential of one agent for pharmacologic therapy for NAFLD/MAFLD.

SR Lieber et al. Liver Transplantation 2021; 27: 1454-1467. What Survivorship Means to Liver Transplant Recipients: Qualitative Groundwork for a Survivorship Conceptual Model

“A majority of LT recipients (75%) identified themselves as survivors. Integral to the definition of survivorship was overcoming hardship (including experiences on the waiting list) and the unique experience of being given a “second chance” at life. Motivations to survive included a new chance at life (55%), family (40%), spirituality/faith (30%), and fear of rejection (15%)”

Does It Matter If Fatty Liver Disease Is Called MAFLD or NAFLD?

H Lee, et al. Clin Gastroenterol Hepatol 2021; 19: 2138-2147. Metabolic Dysfunction-Associated Fatty Liver Disease and Incident Cardiovascular Disease Risk: A Nationwide Cohort Study

A recent study from South Korea with 9.5 million participants (followed for 10 years) shows that changing to metabolic dysfunction–associated fatty liver disease (MAFLD) as a name change from nonalcoholic fatty liver disease (NAFLD) changes the prevalence of at-risk individuals.

Key findings:

  • Prevalence of NAFLD and MAFLD were 28.0% and 37.3%, respectively
  • NAFLD and MAFLD were each associated with significantly higher risk for CVD events: multivariable-adjusted hazard ratios (95% confidence interval) for CVD events were 1.09 (1.03-1.15) in the NAFLD-only group, 1.43 (1.41-1.45) in the MAFLD-only group, and 1.56 (1.54-1.58) in the Both-FLD group
  • In the same issue, a study from Hong Kong showed similar prevalence rates between MAFLD (25.9%) and NAFLD (25.7%) (Clin Gastroenterol Hepatol 2021; 19: 2161-2171). This study noted that many people with hepatic steatosis at baseline have less severe metabolic burden.
  • Also, in the same issue, using a well-define population of more than 13,000 from NHANES III, this retrospective study (Clin Gastroenterol Hepatol 2021; 19: 2172-2181) found that Non-NAFLD MAFLD patients had the highest all-cause and cardiovascular-cause related mortality. In addition, this group had the highest rate of advanced fibrosis >7% (compared to <2% in other groups.

My take (borrowed from authors of first study): “The change from NAFLD to MAFLD criteria may identify a greater number of individuals with metabolically complicated fatty liver and increased risk for CVD.”

Another related article: M Eslam, AJ Sanyal, J George. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease (2020). This article similar to a previous article (Improving Fatty Liver Nomenclature) suggests changing the name for NAFLD to MAFLD.

MAFLD Criteria in this study:

MAFLD is diagnosed based on the presence of hepatic steatosis with one or more of the following:

  1. diabetes mellitus
  2. overweight/obesity (BMI >/= 23)
  3. at least 2 metabolic abnormalities: a) Waist circumference ≥90 cm in men and 80 cm in women. b) Blood pressure ≥130/85 mmHg or under anti-hypertension therapy. c) High-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males and <50 mg/dL for females. d) Triglyceride (TG) ≥150 mg/dL or specific drug treatment. e) fasting glucose ≥100 f) Homeostasis model assessment-insulin resistance (HOMA-IR) score ≥2.5; and g) Hypersensitive C-reactive protein (hs-CRP) level >2 mg/L.

NAFLD Criteria in this study:

The presence of hepatic steatosis without 1. excessive drinking ( ≥30 g/day in men, ≥20 g/day in women) and 2. concomitant liver diseases

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.

Related blog posts:

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.