Tag Archives: NAFLD

How Healthy are “Healthy Volunteers?”

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A recent study (V Takyar et al. Hepatology 2017; 66: 825-33) examined a total of 3160 subjects enrolled in 149 clinical trials from 2011-2015.  These patients were derived from the NIH Clinical Center, ≥18 years, had ALT and BMI measurements available. Presumed NAFLD (nonalcoholic fatty liver disease) was classified if patient had elevated ALT (≥20 for women and 31≥ for men) along with BMI >25 kg/m-squared.

Key findings:

  • 27.9% (n=881) of these healthy volunteers had presumed NAFLD.  These patients also had higher triglycerides, low-density lipoprotein, cholesterol and HbA1c (P<0.001 for all)
  • The authors note that the presence of these presumed NAFLD as controls “likely” affected the study validity in 10 studies and “probably” affected another 41 studies.

My take: This study shows that patients with presumed NAFLD are often enrolled in research studies as healthy controls.  Furthermore, this can affect study outcomes.

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Lover’s Leap, NC -Appalachian Trail

Defining the Role for Elastography

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The ability to determine if a patient has cirrhosis/severe fibrosis with a noninvasive test can help determine appropriate monitoring and treatment for many liver conditions. As such the AGA has provided recommendations for the use of vibration-controlled transient elastography (VCTE).

  • JK Lim et al. Gastroenterol 2017; 152: 1536-43.
  • S Singh et al. Gastroenterol 2017; 152: 1544-77.

Many recommendations are based on the specific unit of measurement, kilopascals (kPa)

Specific recommendations (most with low  or very low quality evidence):

  • “In adults with chronic HCV, we can accurately diagnosis cirrhosis …with VCTE-defined liver stiffness of ≥12.5 (±1) kPa.”  The AGA suggests using VCTE rather than MRE for detection of cirrhosis.
  • “In adults with chronic HCV who have achieved SVR…we can accurately rule out advanced fibrosis (F3 and F4) with post-treatment VCTE-..of ≤9.5 (±1) kPa.” . Even in patients who have had HCV eradicated, if cirrhosis has been identified, careful followup is recommended.
  • “In adults with chronic HBV, we can accurately diagnosis cirrhosis…with VCTE…of ≥11.0 (±1) kPa.”
  • “The AGA makes no recommendation regarding the role of VCTE in the diagnosis of cirrhosis in adults with NAFLD.” For NAFLD, VCTE is not as helpful as with chronic HCV and HBV.  Currently, liver biopsy remains the “gold standard.” However, for noninvasive imaging, “the AGA suggest using MRE, rather than VCTE, for detection of cirrhosis.
  • For adults with suspected compensated cirrhosis, a VCTE of 19.5 or greater can be used “to assess the need for esophagogastroduodenoscopy to identify high risk esophageal varices.”

My take: These elastography recommendations are applicable for adults.  For pediatric patients, these reports suggest that elastography may be helpful in specific circumstances as well.

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Omaha Beach

Increasing Incidence of Hepatocellular Carcinoma in the U.S.

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A recent study (DL White et al. Gastroenterol 2017; 152: 812-20) provide data showing a striking increase in the incidence of hepatocellular carcinoma (HCC). Using data from the US Cancer Statistics Registry which covers 97% of U.S. population, the authors found the following:

  • HCC incidence rose from 4.4 per 100,000 in 2000 to 6.7 per 100,000 in 2012
  • The annual rate of increase was 4.5% from 2000-2009, but then 0.7% annually from 2010-2012
  • The greatest increase occurred in 55-59 year olds (8.9% annually) and 60-64 year olds (6.4% annually)

The main HCC risk factors are HCV, HBV, and alcoholic liver disease, though obesity-associated HCC is emerging as an important risk factor as well.  The highest rates of HCC are seen in southern and western states, with Texas having the highest rates overall.  The high rate in Texas is in part due to the higher rates of HCC in Hispanics.

Overall, the authors indicate that the rising HCC rates are most closely tied to the peak HCV cohort (1945-65) and speculate that the arrival of direct-acting antivirals may help. At the same time, this HCV cohort is composed “disproportionately [of] minorities and of lower socioeconomic status” and may have less access to these advances in treatment.  Furthermore, in states like Texas which did not adopt Medicaid expansion as part of the Affordable Care Act, there are more uninsured patients who will be less likely to identify preceding risk factors for HCC.

My take: Perhaps in 20 years, we will see HCC incidence maps that are improving as HCV treatments become more widely available.  This presumes that other HCC risk factors, including obesity and alcohol, do not worsen significantly.

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Pediatric NAFLD Guidelines 2017

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The concise recommendations (M Vos et al. JPGN 2017; 64: 319-34) from the Expert Committee on NAFLD (ECON)/NASPGHAN provide helpful advice on this increasingly common disorder. Link to full text: NASPGHAN Clinical Practice Guideline for NAFLD

The recommendations are graded on strength of recommendation and quality of the evidence.

Some key points:

  • Use ALT as a screening tool (despite its imperfections). Persistently elevations (>2xULN) should be evaluated for liver disease, including NAFLD.  (Norms: 22 U/L for girls, 26 U/L for boys). Values above 80 U/L “warrants increased clinical concern.”
  • Screening should be considered between ages 9 and 11 years for all obese children and for overweight children with additional risk factors.
  • Ultrasound and CT scans are NOT recommended.
  • Liver biopsy should be considered for the assessment of NAFLD in children who have increased risk of NASH and/or advanced fibrosis.  This could include those with splenomegaly, AST/ALT>1, higher ALT (>80 U/L), panhypopituitarism, and type 2 diabetes.
  • Treatment: Lifestyle modifications recommended.  No currently avaiable medications or supplements are recommended.
  • Look for & avoid comorbidities: dyslipidemias, hypertension, and diabetes. Assure vaccinations against Hep A/Hep B and counsel against binge drinking and against smoking.

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Liver Briefs Feb 2017

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JB Schwimmer et al. Gastroenterol 2016; 151: 1141-54.  Using a double-masked trial with 169 children with NAFLD, the use of cysteamine bitartrate for 1 year did not reduce histologic activity scores, but did reduce liver aminotransferase levels.

NA Terrault et al. Gastroenterol 2016; 151: 1131-40. The authors collected data from 2099 participants in the HCV-TARGET study who mainly received ledpasvir-sofosbuvir (311 received therapy in combination with ribavirin).  The study included 25% blacks, 66% with genotype 1A, 41% with cirrhosis, 50% with prior treatment, and 30% who were receiving proton pump therapy.  Key finding: SVR12 rates varied from 95% to 97% based on duration of therapy.  Factors that predicted SVR12 included higher albumin (>3.5 g/dL), lower total bilirubin (<1.2), absence of cirrhosis, absence of proton pump inhibitor therapy.

KR Olson et al. NEJM 2017; 376: 268-78.  This case report of an 18 yo woman with acute liver failure provides a helpful review.  For Wilson’s disease, the article reviews rapid diagnostic criteria: “a screen that shows a ratio of alkaline phosphatase (IU per liter) to total bilirubin (mg per deciliter) of lower than 4.0 and then subsequently shows a ratio of aspartate aminotransferase (IU per liter) to alanine aminotransferase (IU per liter) of higher than 2.2 has been described as 100% sensitive and specific for the diagnosis of Wilson’s disease.”  Making this diagnosis quickly is crucial and allows these patients to be UNOS status 1A, “the only cause of acute liver faliure that allows a patient with preexisting liver disease to be listed as status 1A”

Among children older than 10 years of age, Wilson's disease accounted for 90% of metabolic disease.

Among children older than 10 years of age, Wilson’s disease accounted for 90% of metabolic disease.

Fatty Liver Improved with Exercise

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A recent study (LA Orci et al. Clin Gastroenterol Hepatol 2016; 14: 1398-1411) analyzed data from 28 randomized trials (>1600 patients) and performed a meta-analysis regarding the utility of exercise for nonalcoholic fatty liver disease (NAFLD).

Key finding:

  • Physical activity, independently from diet change, was associated with improvement in intrahepatic lipid content (-0.69) and with reduction in alanine aminotransferase.

The authors note that the effects of lipid reduction due to exercise is considered moderate-to-large.  In several trials, another effect of exercise that was measured was a reduction in insulin resistance.

Limitations:

  • The duration of the effect of exercise is not known and there is not a clear “dose” of exercise.
  • Lack of histologic data (only 2 studies had histology data)

My take: This study suggests that exercise by improving metabolic status is important in improving NAFLD; thus, a fatty liver is not just about being fat.

Bar Harbor at Sunset

Bar Harbor at Sunset

Prevalence of Diabetes with Pediatric NAFLD

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Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease  (JAMA Pediatr. Published online August 01, 2016. doi:10.1001/jamapediatrics.2016.1971)

According to a a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network and with 675 participants (mean age 12.6 yrs):

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Interesting Fatty Liver Articles -Spring 2016

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J Bousier et al. Hepatology 2016; 63: 764-75.  This study showed an association between the severity of nonalcoholic fatty liver disease and gut dysbiosis/shift in gut microbiome in 57 patients.  Specifically, Bacteroides was independently associated with NASH and Ruminococcus with significant fibrosis.

V WS Wong et al. Hepatology 2016; 63: 754-63. This study showed that NAFLD (identified by ultrasonography screening) was frequent (58.2%) among 612 consecutive patients who were undergoing coronary angiogram. During a followup (3679 patient-years), NAFLD patients had a lower adjusted HR of death (0.36).  Older age and diabetes were indepenently associated with cardiovascular events.  In addition, during f/u NAFLD patients in their cohort rarely developed liver cancer or cirrhotic complications.  Thus, NAFLD is common among patients with coronary artery disease but did not predict a worsened outcome.

F Piscaglia et al. Hepatology 2016; 63: 827-38. This report was a study of 756 patients with liver cancer (HCC) due to either NAFLD (145) or HCV (611). HCC in NAFLD patients had a larger volume, was more infiltrative, and was detected outside surveillance.  NAFLD-HCC was associated with a lower survival (25.5 months compared with 33.7 months for HCV-HCC). The authors note that after patient matching for tumor stage, the survival rate was similar. The difference in survival does not account for lead-time bias (What’s More Important: Improving Mortality Rate or Survival …).  Overall, the study indicates that without surveillance, HCC is detected later.  Due to the frequency of NAFLD, it is unclear which patients would benefit from surveillance and what type of surveillance should be recommended.

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Farjado, Puerto Rico

Farjado, Puerto Rico

 

Overlooking Obesity in Hospitalized Children

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A recent study (MA King et al. J Pediatr 2015; 167: 816-20) shows that physicians and physician trainees rarely addressed overweight/obesity in hospitalized children at a Utah pediatric hospital.

Using a chart review and an administrative database, the authors note that overweight/obesity was identified in 8.3% (n=25) and addressed in 4% (n=12) of 300 hospitalized children with overweight/obesity.  They conclude that “this represents a missed opportunity for both patient care and physician trainee education.”

My take: In many cases, addressing overweight/obesity at a stressful time like a hospitalization may be unwelcome. In children who are not very sick, offering nutritional counseling would be worthwhile.  For others, I think encouraging outpatient followup would be reasonable.

Also noted: “High Prevalence of Nonalcoholic Fatty Liver Disease in Adolescents Undergoing Bariatric Surgery” SA Xanthakos et al. Gastroenterol 2015; 149: 623-34. In this cohort of 242 adolescents, 59% had NAFLD.  None had cirrhosis; stage 3 fibrosis was identified in 0.7%. Comment: I’m surprised that only 59% had NAFLD.

white flower

Days of Future Past and Declining Liver Graft Quality

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In the most recent ‘X-men’ movie (Days of Future Past), the disastrous future is averted by having Wolverine go back in time to correct a mistake. Overall, while there are a good number of movies that have used this trick, this particular movie is pretty clever. For whatever reason, this movie came to mind as I was reading a recent study: “Declining Liver Graft Quality Threatens the Future of Liver Transplantation in the United States” (ES Orman et al. Liver Transpl 2015; 21: 1040-50).  The authors extrapolate data from UNOS to assess what the liver transplantation (LT) picture may look like in 2030. Their results/conclusion:

“If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs.”  “The transplant community will need to accept inferior grafts and potentially worse post transplant outcomes and/or develop new strategies for increasing organ donation.”

The authors note that the national epidemics of diabetes and obesity will result in more cases of NAFLD-related liver failure while at the same time worsen the quality of available grafts. In the associated editorial, (RH Wiesner, pages 1011-12) the author emphasizes that the future is not quite so set.

  • the prevalence of diabetes and obesity in donors for 2030 might not be as great as feared; in addition, medical/surgical advances may diminish the complications associated with obesity
  • there will be a marked decrease in transplants due to hepatitis C virus related cirrhosis and hepatocellular cancer

His conclusion: “in the future, we will be using donor livers that we have never used before and will be achieving similar excellent results as we have today.” Which vision of the liver transplantation future is correct?

Related blog post: AASLD/NASPGHAN 2014 Guidelines for Evaluation of Pediatric …

Bison, Yellowstone

Bison, Yellowstone