Tag Archives: nonalcoholic fatty liver disease

Weight Loss Improves NASH

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A recent study (http://dx.doi.org/10.1053/j.gastro.2015.04.005) helps confirm the notion that the most effective therapy for nonalcoholic steatohepatitis is weight loss. (From Rohit Kohli twitter feed).

Abstract:

Background & Aims

It is not clear how weight loss affects histologic features of liver in patients with nonalcoholic steatohepatitis (NASH). We examined the association between the magnitude of weight loss through lifestyle modifications and changes in histologic features of NASH.

Methods

We conducted a prospective study of 293 patients with histologically proven NASH who were encouraged to adopt recommended lifestyle changes to reduce their weight over 52 weeks, from June 2009 through May 2013, at a tertiary medical center in Havana, Cuba. Liver biopsies were collected when the study began and at week 52 of the diet, and analyzed histologically.

Results

Paired liver biopsies were available from 261 patients. Among 293 patients who underwent lifestyle changes for 52 weeks, 72 (25%) achieved resolution of steatohepatitis, 38 (47%) had reductions in NAFLD activity scores (NAS), and 56 (19%) had regression of fibrosis. At week 52, 88 subjects (30%) had lost 5% or more of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histological parameters (odds ratios, 1.1–2.0;P<.01). A higher proportion of subjects with 5% weight loss or more had NASH resolution (51/88, 58%) and a 2-pt reduction in NAS (72/88, 82%) than subjects that lost less than 5% of their weight (P<.001). All patients who lost 10% of their weight or more had reductions NAS, 90% had resolution of NASH, and 45% had regression of fibrosis. All patients who lost 7%−10% of their weight and had few risk factors also had reduced NAS. In patients with baseline characteristics that included female sex, body mass index ≥35, fasting glucose >5.5 mmol/L, and many ballooned cells, NAS scores decreased significantly with weight reductions of 10% or more.

Conclusions

A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH. The highest rates of NAS reduction, NASH resolution, and fibrosis regression occurred in patients with weight losses of 10% or more.

Fatty Liver at Birth

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A provocative study (Patel KR, White FV, Deutsh GH. JPGN 2015; 60: 152-58) shows that hepatic steatosis/fatty liver is prevalent at birth in at-risk stillborns.

The authors retrospectively examined autospy results from 33 stillborns (20-40 weeks) delivered to women with diabetes (pregestational or gestational) along with 48 age-matched controls.  The majority of women (54%) were African American women; 27% were white and 9% were hispanic.

Key findings:

  • Hepatic steatosis was common and severe in the stillborns of diabetic women.  Prevalence: 78.8% (26/33) compared with 16.6% (8/48) of controls.
  • No direct correlation was identified between steatosis and glycemic control.

Whether nonalcoholic fatty liver disease (NAFLD) begins at birth is not known and what happens to the fat in newborns with hepatic steatosis is not clear.  This study indicates that maternal diabetes may increase the risk of NAFLD.

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Magnetic Resonance Elastography in Nonalcoholic Fatty Liver Disease

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A recent study (Hepatolology 2014; 60: 1920-8) shows that magnetic resonance (MR) elastography can be an accurate noninvasive tool to assess liver fibrosis.

Background: Assessing severity of liver fibrosis provides important prognostic information in patients with nonalcoholic fatty liver disease (NAFLD); however, these patients are often obese which decreases the success of transient elastography.  In addition, high hepatic fat content may alter the results of transient elastography.  Hence, an alternative noninvasive technique is desirable.

Design: Prospective study with 117 consecutive patients with biopsy-proven NAFLD who also underwent 2D-MR elastography between 2011-2013.

Results:

  • Fibrosis stage: stage 0 n=43, stage 1 n=39, stage 2 n=13, stage 3 n=12, stage 4 n=10.
  • MR elastography identified stage 3-4 with an accuracy of 0.92, with little overlap between advanced (F3-4) and non-advanced (F0-2) values.  The specificity, sensitivity, positive/negative predictive values, and cutoff values are detailed in Table 2.
  • Figure 3 provides a cool picture demonstrating the different MR elastography stiffness heat maps correlated with liver fibrosis. Link to similar web-based image from Siemens.

Bottomline: This technology allows a noninvasive measure of liver fibrosis in NAFLD patients and will probably be of use in other liver conditions.  Given the fact that a liver biopsy is more risky and often expensive, this technology and other noninvasive markers of advanced liver disease will be important tools.

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Screening for NAFLD

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As noted in previous blogs (see below), there is not a consensus with regard to screening for NAFLD in overweight and obese patients.  While some have argued for aggressive screening leading to an expensive tiered evaluation, other experts have been reluctant to endorse this approach, in part due to the magnitude of the problem and due to the perceived lack of therapeutic options.  Weighing in on this controversy is a new study (Aliment Pharm Ther 2013; DOI: 10.1111/apt.12518, link -from Jeff Schwimmer’s twitter feed: http://t.co/q1CUKBJtVo).

In the study’s introduction, the prevalence of NAFLD, estimated to be 9.6% of all children aged 2-19 years, along with society guidelines are reviewed.

The authors examined information from the clinical evaluation of 347 children (>10 years) [overweight (7%)/obese (93%)] who were referred by their primary care physician due to either an elevated ALT or suspected NAFLD.  Referral was at the discretion of the primary care attending and not based on a specific ALT value.  Median age was 13.5 years and 64% were boys.

1st tier: Subsequently, all patients underwent hepatic panel, GGT, CBC/diff, and coagulation studies.  2nd tier: If abnormal, the next set of labs may have included any or all of the following: studies for hepatitis infection (HAV, HBV, HCV), HIV, alpha-1-antitrypsin, ANA, anti-smooth muscle antibody, anti-liver kidney microsomal antibody, quantitative IgG, ceruloplasmin,  24-h urinary copper, tissue transglutaminase antibody, serum IgA, serum amino acids, urine organic acids, serum acylcarnitine, creatine kinase, ESR, CRP, and thyroid studies. (The authors did not evaluate iron status.) 3rd tier: Then, if evidence of chronic liver disease, patients were offered a liver biopsy under general anesthesia.

Results:

  • 21% did not have significant liver disease (after 1st tier).  Also, 3 liver biopsies were normal.
  • 94% of 273 with evidence of chronic liver disease underwent liver biopsy; no significant complications were noted, though a small percentage had some discomfort.
  • Ultimately, 55% were determined to have NAFLD (75% of those who underwent liver biopsy.
  • The authors report that 61 patients who had a liver biopsy had another liver disease, including autoimmune hepatitis in 11, celiac disease in 4, sclerosing cholangitis in 1, and drug-induced in 6.
  • Advanced fibrosis was noted overall in 11% (38 of 347) and in 17% of those with NAFLD.  Those with advanced fibrosis were more likely to have higher aminotransferases (eg. ALT 120 U/L compared with 82 U/L), higher GGT, and higher ceruloplasmin; however, there was significant overlap.
  • Approximately half of NAFLD patients had steatohepatitis.

Take-home message: while this article does not resolve the issue of whether screening overweight/obese children is the best strategy, it does provide useful information in those with elevated liver tests.  Careful investigation for treatable causes (and possibly nontreatable) of liver disease is worthwhile in those with sustained abnormalities in transaminases.  At a minimum, tests for autoimmune hepatitis, celiac disease, viral hepatitis, and Wilson’s disease should be at the top of the list.

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Breakthrough for Fatty Liver Disease?

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Could bile acids play a role in reducing metabolic syndrome and in particular fatty liver disease?  This question is now being studied (Gastroenterology 2013; 145: 574-82).

This recent study examined whether obeticholic acid (OCA) which is a semisynthetic derivative of the human bile acid chenodeoxycholic acid could aid with insulin resistance and ultimately nonalcoholic fatty liver disease (NAFLD).  OCA is an agonist of the farnesoid X receptor which is a nuclear hormone receptor that regulates glucose and lipid metabolism.

The authors performed a phase 2, double-blind, placebo-controlled study to assess the effects of OCA on insulin sensitivity in patients with NAFLD and type 2 diabetes mellitus.  Patients received either placebo (n=23), 25 mg OCA (n=20), or 50 mg OCA (n=21) once daily for 6 weeks.  Using an insulin clamp, insulin sensitivity was measured before and after the study period.  Numerous blood tests were obtained as well.

Results:

  • Insulin sensitivity improved 28% in the 25mg OCA group and 20.1% in the 50 mg OCA group whereas it decreased 5.5% in the placebo group.
  • The OCA groups also had significant reductions in gamma-glutamyltransferase, alanine aminotransferase, and dose-related weight loss.
  • Markers of liver fibrosis decreased in the 25 mg OCA group.
  • Side effects of OCA were minimal.  Constipation was reported in the 50 mg OCA group.

Take-home message: OCA may help patients with NAFLD and a bigger, longer study is in the works (FLINT study: 25 mg OCA for 72 weeks compared with placebo, http://www.clinicaltrials.gov; NCT01265498)

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Pediatric Fatty Liver Disease -in the news

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An excerpt from The Wall Street Journal, Fatty Liver Disease: More Prevalent in Children (also covered by this blog previously: Increasing prevalence of pediatric NAFLD | gutsandgrowth):

A type of liver disease once thought to afflict primarily adult alcoholics appears to be rampant in children.

image

Some 1 in 10 children in the U.S., or more than 7 million, are thought to have the disease, according to recent studies.

The condition, in which the normally rust-colored organ becomes bloated and discolored by yellowish fat cells, has become so common in non-drinkers that it has been dubbed nonalcoholic fatty liver disease.

The disease’s prevalence is alarming doctors who worry about its progression to nonalcoholic steatohepatitis, or NASH, when the fatty liver becomes inflamed and cells are damaged. That leads to the end stage of cirrhosis, when the liver forms scar tissue and ultimately stops working.

Organ Damage

Some facts about nonalcoholic fatty liver disease:

  • About 10% of children in the U.S. are thought to have the condition.
  • Several factors likely contribute, including genetics, obesity, diet and insulin resistance.
  • It has no detectable symptoms.
  • Weight loss is the standard treatment for earlier stages of liver disease.

The condition’s rise is tied to the obesity epidemic—about 40% of obese children have it—but isn’t caused solely by being overweight. The disease appears to be growing among normal-weight children too, experts say.

And even though obesity rates are starting to level off, the prevalence of fatty liver disease continues to rise, they say.

It also has no symptoms, which means a person could have it for decades without knowing. 

Full link:

Fatty Liver Disease: More Prevalent in Children

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Low Ceruloplasmin Levels in Pediatric NAFLD

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Pediatric patients with nonalcoholic fatty liver disease (NAFLD) undergo workup to exclude underlying diseases.  For many patients, this may include screening for Wilson’s disease with a ceruloplasmin level.  In a recent study, lower ceruloplasmin in 100 pediatric patients with NAFLD were associated with more severe NAFLD (JPGN 2013; 56: 370-75).

All patients had measurements of copper, iron, ceruloplasmin, transferrin ferroxidase activity, and ferritin; these assays were from archival serum samples from a cohort with biopsy-proven NAFLD. These patients had undergone testing for other etiologies of liver disease.

The authors were trying to determine if oxidative stress and its association with iron or copper may be playing a role in the severity of NAFLD.  Those with lower severity NAFLD score (< 5) had a mean ceruloplasmin of 36.4 mg/dL (standard deviation 5.3); in contrast,  those with higher severity NAFLD score (≥5) who had a mean ceruloplasmin of 28.1 mg/dL (standard deviation 7.2).  That is, there was an inverse association between ceruloplasmin levels and the severity of NAFLD score.  Lower ceruloplasmin was associated with increased inflammation, more ballooning histology, and more steatosis.

Key point:

Lower ceruloplasmin (<28.6 mg/dL) had a 92% specificity and 76% sensitivity for identifying more severe NAFLD.  Thus, even a borderline-low ceruloplasmin that does not suggest Wilson’s disease may be useful in discriminating children more likely to need a liver biopsy.

Related blog entry:

NAFLD Guidelines 2012 | gutsandgrowth

Ultrasound Unreliable to Exclude Fatty Liver

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More information on the sensitivity of ultrasonography for detecting fatty liver is available in the setting of living-related liver transplantation (Transplantation 2013; 95: DOI: 10.1097/TP.0b013e31828d1588).

In this study the authors retrospectively examined the degree of steatosis from 492 living liver donors who had normal ultrasounds and normal aminotransferase levels. The median age of the donors was 30.1 year and the median BMI was 22.4 kg/meter-squared.

Background: According to the authors, if liver histology shows severe macrosteatosis (>60%), transplantation is canceled.  Furthermore, in cases of moderate macrosteatosis (30-59%), the risks/benefits need to be considered on an individual basis due to increased risk of mortality; Spitzer et al (reference below) demonstrated that macrovesicular steatosis >30% was an independent predictor of reduced 1-year graft survival.  In addition, a previous report has indicated that both macrosteatosis and microsteatosis had similar impacts on postoperative  liver function.

Results:

  • 3 (0.6%) had severe total steatosis, moderate or greater steatosis was diagnosed in 4 (0.8%) for macrosteatosis, in 26 (5.3%) for microsteatosis, and 56 (11.4%) for total steatosis.
  • There were two identified risk factors BMI >23 kg/meter-squared and triglycerides >88 mg/dL.  Individuals with both risk factors had a 28.6% prevalence of moderate or greater degree of total steatosis compared with 6.6% with no risk factors.  In these individuals, a liver biopsy may be worthwhile.

Why this study matters for the non-transplant physician:  This study provides additional data that ultrasonography is not adequate to exclude significant degrees of fatty liver.

Study limitations included the retrospective analysis which relied on medical record accuracy, degree of steatosis was not based on a single pathologist, ultrasonography was not based on not based on a single radiologist, both BMI and triglycerides may vary based on age, gender, ethnicity and other factors.

Related blog entries:

Related references:

  • -Spitzer AL et al. Liver Transpl 2010; 16: 874-84.
  • -Liver Transpl 2013; 19: 437-49. Difficulty with precisely determining steatosis
  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -Gastroenterol 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound.

Increasing prevalence of pediatric NAFLD

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A recent study shows that the prevalence of nonalcoholic fatty liver disease (NAFLD) in adolescents has increased over a 20 year period in the U.S. (J Pediatr 2013; 162: 496-500).

Using a cross-sectional data from 12,714 adolescents, aged 12-19, from the National Health and Examination survey, the prevalence of suspected NAFLD has more than doubled over the past 20 years and currently affects nearly 11% of adolescents.  Approximately one-half (48%) of obese males have NAFLD.

Suspected NAFLD was defined as elevated ALT in an overweight or obese child.  Specific ALT values were chosen using sex-specific cut points (>25.8 U/L for boys and >22.1 for girls).

  • Besides increased NAFLD, the prevalence of obese BMI (≥95%) and severe obesity (BMI ≥99%) also increased steadily.  Between 1988-1994, obese BMI accounted for 11.2% and severe obese BMI 1.5%.  By 2007-2010, these increased to 20.% and 5.5% respectively.
  • For suspected NAFLD, in 1988-94 compared to 2007-2010, the prevalence went from 3.9% to 10.7%.

Probably the biggest limitation of this study was considering “suspected NAFLD” only in overweight or obese children.  The authors chose to do this to increase the specificity of their diagnosis and avoid overestimating the prevalence of NAFLD.

Related blog posts:

NAFLD Guidelines 2012 | gutsandgrowth

Pediatric NAFLD histology score | gutsandgrowth