Online Aspen Webinar (Part 6) -NAFLD and NASH

Aspen Online Webinar July  14-16, 2020

Below I’ve included some of my notes and slides.  There may be errors of omission or transcription.

What’s Hot? NAFLD and NASH Stavra Xanthakos

  • Fatty liver disease burden of NAFLD and NASH is increasing.  This increases the rate of cirrhosis, liver cancer and liver transplantation; the latter is being needed at younger ages
  • Explained that “Lean” (normal BMI) NAFLD is common
  • Diabetes is strongest risk factor for severe fatty liver disease (NASH or fibrosis). PNPLA3 is genetic risk factor for NAFLD risk.
  • Discussed treatment, particularly diet  and bariatric surgery.  Stated that some emerging treatments look promising.
  • In those with suspected NAFLD, Dr. Xanthokos recommends liver biopsy, if lifestyle therapy is ineffective, under specific circumstances: prior to bariatric surgery, in some cases to determine severity, and prior to instituting therapy (eg Vitamin E)


Related blog posts:

Days of Future Past and Declining Liver Graft Quality

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

Can Apple Make Research Cool?

For anyone who has looked at Apple’s March presentation, there is big news with regard to research (thanks to Seth for this information).  Here’s a link to the March announcement –around minute 16 there is the research presentation: Apple March Event

Screenshot: Rationale for Apple iPhone for Research -Large Research Pool

Screenshot: Rationale for Apple iPhone for Research -Large Research Pool

The presentation makes it clear that Apple wants to dramatically increase the participation in research studies by leveraging 700 million iPhone users.  Using an app called, “ResearchKit”, Apple has partnered with leading academic centers to help study Parkinson’s, Diabetes, Asthma, Cardiovascular disease, and Breast Cancer.  For the GI community, I hope that someone will work collaboratively to add inflammatory bowel disease to the list.

Besides increased participation, iPhone-based research has the ability to lower research costs, collect data at frequent intervals, and allow a wider demographic representation.

A shorter ~4 minute video on a separate area of the website explains ResearchKit: ResearchKit video

 Screenshot: Research Kit

Screenshot: ResearchKit

NBC News provides a condensed summary along with the caveat that there will be concerns about accuracy of data collected with ResearchKit.  That being said, most critics have not always appreciated the impact of previous Apple innovations.

Has someone from our national organization (NASPGHAN) or from ImproveCareNow started working with Apple? If not, this looks like a great opportunity.

Walking with a “Z” or an “X”

In a number of media outlets, there has been a push for a highly successful (and under appreciated) treatment: walking.


  • No/Low cost
  • Easy
  • Often fun
  • Excellent side effect profile

Here’s a link (Every Body Walk!) and here’s an excerpt:

Researchers have discovered a “wonder drug” for many of today’s most common medical problems, says Dr. Bob Sallis, a family practitioner at a Kaiser Permanente clinic in Fontana, California. It’s been proven to help treat or prevent diabetes, depression, breast and colon cancer, high blood pressure, cardiovascular disease, obesity, anxiety and osteoporosis, Sallis told leaders at the 2013 Walking Summit in Washington, D.C.

“The drug is called walking,” Sallis announced. “Its generic name is physical activity.”

Recommended dosage is 30 minutes a day, five days a week, but children should double that to 60 minutes a day, seven days a week. Side effects may include weight loss, improved mood, improved sleep and bowel habits, stronger muscles and bones as well as looking and feeling better.

Comment: If only “walking” was marketed better.  Physicians know that successful treatments need to have an “x” or a “z” or both to really do well (“X and Z in favor”).




Pancreas Transplantation -Moving Personal Story

A recent lengthy article describes the story of one man’s wait and ordeal after pancreas transplantation (due to diabetes).  This article, written as a first-person account by a Cincinnati reporter, provides a detailed view from the patient’s viewpoint of both medical aspects and the social/emotional aspects of undergoing a transplantation.

Here’s the link, from USA Today: John Faherty, “How an Organ Transplantation Changed My Life.”

Breakfast: a marker for heart-healthy habits

Summary of study (Circulation 2013; 128: 337-343) from Epocrates (emphasis in blue by blog):

Study Question:
Is eating breakfast or not associated with risk for coronary heart disease (CHD) among men residing in the United States?
Data for this analysis were from the Health Professionals Follow-up Study, an ongoing prospective study of male health professionals. Approximately 97% of participants were of white European descent. Eating habits, including breakfast eating, were assessed in 1992 in 26,902 American men, ages 45-82 years, who were free of cardiovascular disease and cancer. Participants were followed through mailed biennial questionnaires that ascertained medical history, lifestyle, and health-related behaviors. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for CHD, adjusted for demographic, diet, lifestyle, and other CHD risk factors.
Participants who did not report eating breakfast were younger than those who did, and were more likely to be smokers, to work full-time, to be unmarried, to be less physically active, and to drink more alcohol. Men who reported that they ate late at night were more likely to smoke, to sleep <7 hours a night, or to have baseline hypertension compared with men who did not eat late at night. The late-night eating abstainers were more likely to be married and to work full-time, and ate on average one time less per day than the late-night eaters. The mean diet quality of the participants was high among participants, regardless of their breakfast or late-night eating status. During 16 years of follow-up, 1,527 incident CHD cases were diagnosed. Men who skipped breakfast had a 27% higher risk of CHD compared with men who did not (relative risk, 1.27; 95% confidence interval, 1.06-1.53). Compared with men who did not eat late at night, those who ate late at night had a 55% higher CHD risk (relative risk, 1.55; 95% confidence interval, 1.05-2.29). These associations were mediated by body mass index, hypertension, hypercholesterolemia, and diabetes mellitus. No association was observed between eating frequency (times per day) and risk of CHD.
The investigators concluded that eating breakfast was associated with significantly lower CHD risk in this cohort of male health professionals.
These data suggest that time of meals is associated with other lifestyle behaviors. Adjustment for body mass index, hypercholesterolemia, hypertension, and diabetes [resulted in the relationship between breakfast (and late-night meals) and CHD no longer being significant.] Physicians may use this information to assist in the identification of those who may be at risk and need to improve lifestyle habits. However, it is unlikely that eating breakfast by itself would confer significant protection against heart disease.

Full text available at

Related blog post:

Skipping breakfast –boomerang effect for obesity | gutsandgrowth

Global Disease Burden

In 1991, the World Bank and the World Health Organization launched the Global Burden of Disease Study.  A recent article reviews the key findings (NEJM 2013; 369: 448-57).

The goals of the study are to compare the burden of one disease with others; as such, it is “necessary to consider the age at death and life expectancy of persons affected by each disease and to take account of the degree of disability (eg. discomfort, pain, or functional limitations.”  A comprehensive measure of disability, disability-adjusted life-years or DALYs, was used for comparisons.

The study examined 291 types of diseases and injuries as well as 67 risk factors in 187 countries, looking at the years 1990, 2005, and 2010.


  • In 2010, there were 2482 million DALYs which is a decrease of 0.6% from 1990.  On the basis of population growth, DALYs would have increased by 37.9% without improvements in disease burden.
  • Major causes of death in 2010: Ischemic heart disease-far ahead #1 (21.1% of deaths, 7850 thousand DALYs), Stroke (6.5% of deaths, 2574 thousand DALYs), Lung/airway cancer (6.1% of deaths, 3033 thousand DALYs), Alzheimer’s (5.9% of deaths, 2022 thousand DALYs), COPD (5.8% of deaths, 3659 thousand DALYs).
  • Global DALYs in 2010 (top ten -starting with #1): Ischemic heart disease, Lower respiratory tract infections, stroke, diarrhea, HIV-AIDs, Malaria, Low Back pain, Preterm birth complications, COPD, and road-traffic injury.
  • Top risk factors (starting with #1): High blood pressure, tobacco smoking (including 2nd-hand smoke), household air pollution, diet low in fruit, alcohol use, high body-mass index, high fasting plasma glucose level, childhood underweight, exposure to outside pollution, physical inactivity, diet high in sodium

Since 1990, there has been a shift.  “In general, communicable, maternal, neonatal, and nutritional conditions decreased in absolute terms.”  The main exceptions were HIV and malaria. Noncommunicable diseases, especially diabetes, have been increasing in terms of percentage and absolute numbers.

Another important change has been a relative increase in disability compared with premature death.  In addition, of the “top 25 causes of years lived with disability, only COPD, diabetes, road-traffic injury, ischemic heart disease, and diarrhea are also among the tope 25 causes of years of life lost.”  “What ails most persons is not necessarily what kills them.”

Bottom-line: While collecting this type of data has many potential limitations, the broad picture it provides should help inform policymakers with priorities for research and intervention.  This data also allows the US to benchmark its efforts compared to other countries.  For example, according to the authors, currently the US has the best global performance with respect to stroke and the worst with respect to lung cancer and Alzheimer’s disease; however, “data and analyses are lacking to elucidate the drivers of these changes in relative performance.”

Preventing Type 2 Diabetes

A ‘perspective’ article reviews data from several studies that show the efficacy of medical treatments aimed at preventing type 2 diabetes (NEJM 2012; 367: 1177-79).

The Diabetes Prevention Program (DPP) was a comparative effectiveness trial of 3234 overweight or obese adults with impaired glucose tolerance (prediabetes).  Findings from this study (published in 2002) showed that lifestyle intervention (attempts at weight loss through diet and exercise) reduced conversion to diabetes by 58% over 3 years, whereas metformin reduced this conversion by 31% over 2 years.  Lifestyle intervention worked best in patients ≥ 60 years.

Subsequently, 88% of these subjects were enrolled in the 10-year outcome study (DPPOS).  The lifestyle intervention group had a 31% 10-year reduction in diabetes compared with 18% for metformin.

The editorial points out that there have been efforts to expand these results across the country through CDC-sponsored programs in cooperation with the YMCA and UnitedHealth.

Potential roadblocks remain:

  • Most payers do not cover these preventive services.
  • US Preventive Services Task Force (USPSTF) has not issued a recommendation on these services.  this affects both public and private insurance coverage.
  • Metformin which may be useful in younger populations does not have a specific indication for diabetes prevention from the FDA (off-label use only).

Whether prevention is ‘worth a pound of cure’ may be hard to discern with prediabetes.    Since the peak incidence of diabetes is between 50 and 60 years and complications often emerge more than a decade later, the benefits of preventing diabetes may not be fully apparent for quite a long time.

Related blog entries:

Treating diabetes with surgery | gutsandgrowth

Lower leptin with physical activity | gutsandgrowth

Staggering cost of obesity | gutsandgrowth

Staggering cost of obesity

For a single individual, the burden of obesity can be enormous; for a society, the projected costs for health and economics are hard to fathom (Lancet 2011; 378: 815-25).

By 2030, this report projects that there will be 65 million more obese adults in the US and 11 million more in the UK.  This is expected to cause an additional  6-8.5 million cases of diabetes, 5.7-7.3 million cases of heart disease/stroke, about 500,000 cases of cancer, and loss of 26-55 milion life years.  The medical costs are estimated to increase $48-66 billion/year in the US.

These projections are based on expected increases in the percentage of individuals who are obese.  In 2008, approximately 32% of US adult men were obese based on BMI; in 2030, the projected number is 50-51% for men.  Among US women: 35% in 2008 –> 45-52% in 2030.

To flatten the curve on spending, we will need to look at flattening other curves.

Additional references:

  • A liver disease tsunami
  • -NEJM 2011; 365: 1597. Persistence of hormonal adaptations with weight loss. Due to persistent changes in hormones like leptin & peptide YY, hard to keep wt off -result is increased appetite.
  • -NEJM 2009; 360: 859. Composition of diet does not seem to be important. Total calories important.
  • -Pediatrics 2007; 120: suppl 4: S164-S287.
  • -NEJM 2007; 357: 370. obestiy spreads in social network.  Your friends may be more influential than your genetics.
  • -Gastroenterology 2007; 132: 2085-2276. Special issue on obesity issues.
  • -NEJM 2006; 355: 1593. Case review on obesity c DDx and mgt.
  • -Pediatrics 2003; 112: 424. Position paper on prevention in childhood.
  • -Gastroenterology 2001; 120: 669-681. (review)
  • -J Pediatr 2005; 147: 429. TV viewing predicts adult BMI.
  • -Lancet 2001; 357: 505-8. One extra soda/day incr risk of obesity by 60%
  • -NEJM 1999; 341: 1097. BMI & mortality.

Common to be “D-ficient”

Many of the children that a pediatric gastroenterologist sees are at risk for Vitamin D deficiency, including children with inflammatory bowel disease, cystic fibrosis, celiac disease, and liver diseases.  In addition, vitamin D deficiency is widespread: in U.S. 50% of children aged 1-5 years and 70% 6-11 years are vitamin D deficient or insufficient. A thorough review on this “D-lightful” vitamin was in a recent JPEN (JPEN J Parenter Enteral Nutr 2012; 9S-19S).

History: In 1822 Sniadecki recognized children in urban but not rural Poland developed rickets. He postulated the effects of the sun as the reason for rickets; his idea was dismissed.  In 1920s, the concept of irradiating milk to prevent rickets emerged. In 1950s, outbreak of hypercalcemia in infants in Great Britain was thought to be related to vitamin D fortification and curtailed this practice in Europe.  However, these cases were likely due to Williams syndrome.

Sources of vitamin D: oily fish (salmon), cod liver oil, some mushrooms, egg yolk, & sunlight. Exposure of an adult in a bathing suit to one minimal erythemal dose (MED) is equivalent to ingesting 20,000 IUs of Vitamin D. (The minimal dose that induces any visible reddening at that point is defined as one MED.)

Effect of sunscreen: A sun protection factor (SPF) of 30 absorbs approximately 98% of solar ultaviolet radiation & thus lowers vitamin D production by 98%.

Ethnicity: Melanin is an effective SPF.  A person of african-american descent, on average, has an SPF of 15, which reduces vitamin D production by 90%.

Age: Aging decreases 7-dehydrocholesterol in human skin.  Due to this, the elderly produce much less vitamin D.  For example, a 70 year old has a 75% reduction compared to a 20 year old.

Forms of vitamin D:  25-hydroxyvitamin D (25OH-D) is the major circulating form of vitamin D & physicians measure 25OH-D. 25OH-D is metabolized in kidney to 1,25-dihydroxyvitamin D (1,25OH-D), also called calcitriol.  This is the most biologically-active and is responsible for increasing intestinal calcium absorption and mobilizing calcium from bone.  However, 1,25OH-D provides no information vitamin D deficiency; it can be elevated or normal in deficiency states.

  • Cholecalciferol (vitamin D-3) is formed in the skin from 5-dihydrotachysterol.
  • Ergocalciferol (Vitamin D-2) is the form in Drisdol (8000 IU/mL) & Ergocalciferol Capsules (1.25 mg =50,000 USP Units)

Vitamin D deficiency:  The exact numbers are debated.  The institute of medicine (IOM) has considered individuals deficient if 25OH-D is <20 ng/mL.  The Endocrine Society and the author suggest vitamin D deficiency as <20 ng/mL & insufficiency as <30 ng/mL.  The author recommends ideal levels between 40-60 ng/mL.

Consequences of deficiency:

Osteoporosis, Osteopenia, Rickets (see references below): Bone weakening occurs due to loss of phosphorus from the kidneys.  Vitamin D deficiency lowers accrual of calcium in skeleton and leads to osteoporosis, osteopenia, and rickets. Imaging for rickets: the best single radiographic view for infants and children younger than 3 years is an anterior view of the knee that reveals the metaphyseal end and epiphysis of the femur and tibia. This site is best because growth is most rapid in this location, thus the changes are accentuated.

Nonskeletal consequences: vitamin D deficiency is associated with increased risk for preeclampsia, URIs, asthma, diabetes (type 1), multiple sclerosis, hypertension, and schizophrenia.


  • Infants who are breastfed should be receiving supplemental vitamin D, 400 IU/day.
  • Adults/children (>1 year) RDA 600 IU/day –mostly from diet per IOM. Yet author states, “it is unrealistic to believe that diet alone can ….provide this requirement.”
  • In vitamin D deficient patients: (initial treatment) 2000 IU/day or 50,000 IU/week for 6 weeks.
Toxicity from vitamin D (from NEJM 2010; 364: 248-254.): “Toxicity from vitamin D supplementation is rare and consists principally of acute hypercalcemia, which usually results from doses that exceed 10,000 IU per day; associated serum levels of 25-hydroxyvitamin D are well above 150 ng per milliliter (375 nmol per liter). The tolerable upper level of daily vitamin D intake recently set by the Institute of Medicine (IOM) is 4000 IU.”

Additional references:

  • -Pediatrics 2008; 122: 398. Should give 400 IU/day to breastfed babies. Consequences of Vit D deficiency: increased risk for DM, multiple sclerosis, cancer (breast, prostate,colon), rickets, and schizophrenia. Article lists vit D content of foods (high in cod liver oil, shrimp, fortified milk, many fish). Severe deficiency when < 5ng/mL, deficient if < 15 ng/mL; probably should be >32 ng/mL. Causes of vit D deficiency: decreased synthesis (due to lack of sun -skin pigmentation, sunscreen/clothing, geography, clouds), decreased intake, decreased maternal stores & breastfeeding, malabsorption (eg celiac, CF, EHBA, cholestasis), increased degradation; treatment of rickets: double-dose of vitamin d (~1000 IU/day for babies & 5000 for older kids) x 3-4 months along with calcium (30-75/mg/kg/day). Follow Ca/phos/alk phos monthly. Alternatively, give ~100,000 units over 1-5 days.
  • -JPEN J Parenter Enteral Nutr. 2011;35:308-316-Results: The study included 504 IBD patients (403 Crohn’s disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with lower HRQOL (regression coefficient –2.21, 95% confidence interval [CI], –4.10 to –0.33) in CD but not UC (regression coefficient 0.41, 95% CI, –2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). Conclusions: Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.
  • -JPGN 2011;53: 361. similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for bone disease with inflammatory bowel disease.
  • -Pediatrics 2010; 125: 633. Increasing Vit D deficiency noted in minority children. n=290. 22% w levels <20, 74% <30.
  • -Hepatology 2011; 53: 1118. Good vitamin D levels are another favorable predictive factor in antiviral response to Hep C along with IL28B.
  • -NEJM 2010; 364: 248-254. Vitamin D insufficiency. Levels between 20-30 may be OK -not enough evidence to determine conclusively whether this level is detrimental
  • -J Pediatr 2010; 156: 948. High rate among african americans with asthma, 86%. n=63.
  • -Pediatrics 2009; 124:e362. n=6275. 9% of pediatric patients vit D deficient & 61% were insufficient.
  • -Pediatrics 2009; 124:e371. n=3577. low 25OH-D levels inversely assoc with SBP/metabolic syndrome.
  • -NEJM 2009; 360: 398. case report of rickets
  • -J Pediatr 2003; 143: 422 & 434
  • -Pediatrics 2003; 111: 908. 200 IU Vit D recommended for all breastfed infants.
  • -J Pediatr 2000;137: 153 & 143.. Nutritional rickets–primarily in blacks; rec vitamin D 400 IU per day.