National Institute of 

Diabetes and Digestive 

and Kidney Diseases 

NIDDK 

Recent Advances & Emerging Opportunities 

January 2024 

Digestive Diseases 

and Nutrition 

This is a chapter from the NIDDK’s Annual Report. The full Report includes highlights of research on 

these and many other areas across the NIDDK’s mission and is available at: 

www.niddk.nih.gov/about-niddk/strategic-plans-reports/niddk-recent-advances-emerging-opportunities

U.S. Department of Health and Human Services 

National Institutes of Health 

National Institute of Diabetes & Digestive & Kidney Diseases 
Digestive Diseases and Nutrition TOC 2024

NIDDK Recent Advances & Emerging Opportunities 2024

DIGESTIVE DISEASES AND NUTRITION...........55 

Exploring Intestinal Function in 

Health and Disease ....................................................58 

Signals Between Nervous System and 

Intestinal Cells Control Protective 

Mucus Layer Production in Gut.......................58 

A Link Between Cellular Stress 

and Gut Inflammation........................................58 

The Complex Interplay of

Diet and the Gut Microbiome Influences

Human Health......................................................59 

Understanding Inflammatory Bowel Disease.......59 

Uncovering Biological Links Between 

Stress and Inflammatory Bowel 

Disease Flare-Ups...............................................59 

Expanded Study Diversity Uncovers 

New Genetic Risk Factors for

Inflammatory Bowel Disease ...........................60

Impacts of Pancreatitis Pain.....................................61 

Pain Linked to Lower Physical and Mental

Health in People with Chronic Pancreatitis....61 

Preventing and Treating Liver Disease...................62

Limits on Acetaminophen in 

Acetaminophen-Opioid Combination 

Medications Affected Causes of

Acute Liver Failure..............................................62

Disrupting “Talk” Amongst Liver Cells 

Yields Therapeutic Targets for

Nonalcoholic Fatty Liver Disease ....................62

Optimizing Treatment Regimens for

Adults With Chronic Hepatitis B.....................63 

Connecting the Microbiome and Liver Diseases.....64

Complex InterplayAmong Gut, Liver, 

and Microbes Underlies Metabolic 

Changes in Chronic Hepatitis C.......................64

The Yin and Yang of Microbial Influences 

on the Liver Disease Primary

Sclerosing Cholangitis .......................................64

Feature: Research Aims to “Triumph”Against

Childhood Liver Disease................................................. 66 

Feature: Making New Connections to

Address the Silent Epidemic of

Nonalcoholic Fatty Liver Disease ................................. 68 

Personal Perspective: Advancing

Research to Improve the Health of

People With Pancreatitis................................................ 72
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 55

The nervous system in the gut—such as the neurons (shown in red) and glia (shown in green) in the microscopy 

image above—relays signals between the brain and the immune system. As described in this chapter, scientists have 

demonstrated that stress exacerbated intestinal inflammation in different mouse models of inflammatory bowel 

disease (IBD) and found evidence for the specific molecular pathways responsible. The researchers found evidence 

that these pathways likely play the same role in IBD in people as well, a finding that sheds light on the underlying 

mechanisms linking stress to IBD flare-ups.

Image used courtesy of the lab of Dr. Christoph Thaiss, University of Pennsylvania. Image credit: Markus Schneider, Klaas Bahnsen, and Niklas Blank. 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 56

Digestive diseases can exact a significant toll on 

individuals across the lifespan, resulting in a lower 

quality of life, years lost due to premature death, and 

costs associated with hospitalization and pharmaceutical 

and surgical interventions. The burden of digestive 

diseases in the United States is substantial: based on 

recent data, it is estimated that digestive disease is the 

primary diagnosis in a total of 66.4 million ambulatory 

care visits to physicians’ offices and hospital emergency 

and outpatient departments in the United States each 

year.1 Similarly, analyses with 2020 national inpatient 

samples identified 3.5 million hospitalizations with a 

primary diagnosis of digestive diseases and 15.1 million 

hospitalizations with a primary or secondary diagnosis 

of digestive diseases.2 In addition, analyses focusing 

specifically on the clinical and economic burden of 

emergency department visits identified 15.5 million 

emergency department visits with a primary diagnosis 

of digestive diseases and costs totaling $113 billion 

in 2020.3 (Note that the 2020 statistics are likely 

underestimates due to pandemic-related health care 

challenges.)

Inflammatory bowel disease (IBD), an umbrella term 

for chronic and painful intestinal diseases that include 

Crohn’s disease and ulcerative colitis, is marked by 

damaging intestinal inflammation that can cause rectal 

bleeding, diarrhea, nutritional deficiencies, and other 

serious complications. IBD often strikes early in life, 

with a peak age of onset in adolescence or young 

adulthood. The continued discovery of predisposing 

genetic variations, potential autoimmune and microbial 

influences, and new methods to repair damaged 

intestinal tissue will help predict the best course of 

treatment and catalyze the design of novel, more 

personalized therapeutic strategies.

Diseases of the stomach and intestines also include 

peptic ulcer disease, which is typically caused by 

infection with the bacterium Helicobacter pylori or 

use of nonsteroidal anti-inflammatory drugs. Other 

stomach and intestinal disorders include functional 

Digestive diseases are among the leading causes of doctor visits, hospitalizations, and 

disability in the United States each year. These conditions span a wide spectrum of disorders 

that affect the gastrointestinal (GI) tract, liver, gallbladder, and pancreas, as well as obesity 

and other nutrition-related disorders. To reduce the burden of digestive diseases, NIDDKsupported scientists are pursuing research to better understand how widespread these 

diseases are across the United States and in specific population groups; identify their causes 

and how they progress; and test new interventions for prevention and treatment, including 

drugs, surgery, and behavior modification.

Digestive Diseases and Nutrition

1

 Centers for Disease Control and Prevention. National Ambulatory Medical 

Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey 

(NHAMCS). http://www.cdc.gov/nchs/ahcd/index.htm. Accessed October 17, 

2023. 

2 Agency for Healthcare Research and Quality. Healthcare Cost and Utilization 

Project (HCUP) National Inpatient Sample (NIS). http://www.hcup-us.ahrq.

gov/nisoverview.jsp. Accessed October 17, 2023. 

3 Agency for Healthcare Research and Quality. Healthcare Cost and Utilization 

Project (HCUP) Nationwide Emergency Department Sample (NEDS). http://

www.hcup-us.ahrq.gov/nedsoverview.jsp. Accessed October 17, 2023.

Annual estimates of the burden of digestive 

diseases list these diseases as the primary 

diagnosis in 66.4 million ambulatory care visits 

to physicians’ offices and hospital emergency 

and outpatient departments.

Scientists are investigating the complex 

interactions among the genetic, 

environmental, immune, microbial, and other 

factors that contribute to, or protect against, 

the development of inflammatory bowel 

disease.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 57

GI disorders, such as irritable bowel syndrome (IBS), 

which can cause abdominal pain and altered bowel 

habits. Gastroesophageal reflux disease, in which caustic 

stomach acids rise up into the esophagus, can lead to 

a heightened risk of esophageal cancer. Gastroparesis 

is characterized by delayed emptying of food from the 

stomach, resulting in nausea, vomiting, and abdominal 

discomfort. Fecal incontinence, or impaired bowel 

control, is a very prevalent condition, and because it 

is difficult to talk about, many people suffer without 

seeking treatment. Scientists continue to strive for a 

deeper understanding of the causes of GI disorders, 

which will lead to improvements in diagnosis and 

management. 

In individuals with celiac disease, the immune system 

reacts to ingestion of gluten—a protein component of 

wheat, barley, and rye—resulting in chronic diarrhea, 

bloating, anemia, and, in children, slower growth and 

short stature. The only current treatment for celiac 

disease is maintenance of a strict gluten-free diet, which 

is difficult for many people. Research advances in the 

understanding of genes and environmental triggers that 

are involved in the development of celiac disease may 

contribute to improved diagnosis and treatment.

The microbes that inhabit the GI tract—also known as 

the intestinal microbiome—are important in maintaining 

the balance between digestive health and disease. 

These bacteria, viruses, and other microorganisms can 

affect long-term health and nutritional status, depending 

on their interactions with each other, with intestinal 

cells, and with nutrients ingested by their human host. 

Disruptions in this microbial ecosystem are associated 

with diseases such as IBD or infections by the harmful 

bacterium Clostridium difficile. Scientists are gaining 

insights into the ways these GI microbes influence the 

development and function of the digestive tract and 

other systems throughout the body, such as those with 

immune and metabolic functions, as well as how the 

composition of the GI microbial community changes with 

factors such as age, geography, diet, and antibiotic usage. 

In acute and chronic pancreatitis, digestive enzymes 

attack the pancreas from within, causing inflammation, 

loss of function, and severe pain. Advanced pancreatitis 

can be debilitating and may lead to cancer or diabetes, 

and because pancreatitis is difficult to detect in its early 

stages, many cases are advanced by the time they are 

diagnosed. Research has elucidated genetic and other 

factors contributing to pancreatitis that may lead to ways 

to treat or prevent this disease. 

Serious adverse health effects can occur when the liver is 

functionally compromised by disease, which sometimes 

leads to scarring. Severe scarring (cirrhosis) can result 

in complete liver failure (end-stage liver disease). Some 

liver diseases primarily affect children, such as biliary 

atresia (a progressive inflammatory liver disease), while 

others generally affect adults, such as nonalcoholic 

fatty liver disease (NAFLD) or its more severe form, 

nonalcoholic steatohepatitis. In recent years, however, 

NAFLD in the United States has been increasingly 

diagnosed in children as well, concurrent with rising rates 

of overweight and obesity. NAFLD is also associated 

with health disparities: while the disease occurs in 

people of all races and ethnicities, in the United States 

it is more likely to affect those of Hispanic ethnicity. 

Some forms of liver disease are caused by viral infection, 

as in most cases of hepatitis, or by genetic mutations 

such as alpha-1-antitrypsin deficiency; others arise from 

factors such as autoimmune reactions, drug toxicity, bile 

duct obstruction, and other triggers, some of which are 

unknown. Many liver diseases, such as chronic hepatitis 

B and C, place individuals at elevated risk for developing 

liver cancer. When liver disease reaches the end 

stage, the only effective treatment is a liver transplant. 

Research is critical to identify liver disease early, find 

methods to preserve liver function in people with liver 

disease, and develop and further study new treatment 

options, including experimental, cell-based approaches 

to liver regeneration.

NIDDK also funds research on nutrition-related 

disorders that involve specific, inherited alterations in 

nutrient metabolism. NIDDK-supported research has 

enhanced knowledge of how these nutritional disorders 

develop and how they can best be treated. Investigators 

also conduct basic, clinical, and translational research 

on the requirements, bioavailability, and metabolism of 

Research to advance understanding of genes 

and environmental triggers involved in the 

development of celiac disease may contribute to 

improved diagnosis and therapy.

In recent years, nonalcoholic fatty liver disease 

has been increasingly diagnosed in children and 

adults in the United States, concurrent with 

rising rates of overweight and obesity.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 58

nutrients and other dietary components to understand 

dietary needs in health and disease. NIDDK staff work 

collaboratively with representatives from across NIH, 

including in NIH’s Office of Nutrition Research, to 

advance nutrition research efforts.

EXPLORING INTESTINAL FUNCTION IN 

HEALTH AND DISEASE

Signals Between Nervous System and Intestinal Cells 

Control Protective Mucus Layer Production in Gut: 

New research in mice has discovered connections 

between the nerve cells of the gastrointestinal tract and 

mucus production in the gut, pointing to a role for these 

nerves in protecting the intestinal lining from damage and 

inflammation. Inflammation in the gut (e.g., colitis) can 

cause abdominal pain, a hallmark of many gastrointestinal 

diseases and disorders. Pain-sensing nerve cells—called 

nociceptors—envelop the gut, however their interactions 

with the cells of the gut itself are not fully understood. 

By better understanding the “cross-talk” between these 

cells, researchers could find new ways to help resolve the 

inflammation or to protect the intestines from further 

damage. It could also help scientists understand and 

treat painful gastrointestinal conditions like inflammatory 

bowel disease.

Researchers working with a mouse model recently 

found that nociceptors come into close contact with 

goblet cells—cup-shaped cells in the intestinal lining that 

secrete mucus to coat the inside of the gut—suggesting 

that signals from nociceptors might control mucus 

production. The mucus layer provides nutrients and a 

habitat for bacteria that aid digestion. It also creates 

an important physical barrier to protect the gut from 

those bacteria, so mucus production is critical for both 

preventing intestinal damage and maintaining a healthy 

microbiome. The researchers found that male and 

female mice that were genetically engineered to lack 

nociceptors had thinner mucus layers on their intestinal 

linings compared to mice with an intact intestinal 

nervous system, demonstrating that nociceptors do 

indeed control mucus production. The researchers also 

found that capsaicin (the “spicy” chemical in peppers) 

or products from gut bacteria triggered the release of 

a chemical signal called calcitonin gene-related peptide 

(CGRP) from nociceptors, and the goblet cells responded 

to this signal by secreting mucus. This means that when 

the gut is exposed to potentially damaging agents—either 

from the diet or bacteria—nociceptors can bolster the 

gut’s defenses by stimulating more mucus production. 

Not surprisingly, the mice with thinner mucus layers also 

had disrupted microbiomes and were more susceptible 

to experimentally induced intestinal inflammation 

(colitis), but the mice were protected from inflammation 

when the researchers administered CGRP to compensate 

for the lack of nociceptors. 

These results identify a pathway whereby nociceptors 

can sense insults to the gut and respond not only with 

pain but also with a signal to help protect the gut. More 

work is needed to confirm that a similar pathway exists 

in humans, but these insights could help researchers 

develop new ways to treat intestinal inflammation and 

abdominal pain while minimizing disruptions to the 

intestinal barrier. 

Yang D, Jacobson A, Meerschaert KA,...Chiu IM. Nociceptor neurons direct 

goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut 

barrier protection. Cell 185: 4190-4205, 2022.

A Link Between Cellular Stress and Gut Inflammation:

Scientists determined how a state of cellular stress in the 

inner lining of the gut promotes production of a type of 

immune cell linked to chronic inflammatory diseases. The 

inner lining of the gastrointestinal tract, called the intestinal 

epithelium, absorbs nutrients into the body and acts as a 

barrier restricting entry of harmful factors. Damage to the 

intestinal epithelium plays a role in chronic inflammation 

and development of inflammatory bowel diseases such 

as Crohn’s disease and ulcerative colitis. Understanding 

how a healthy intestinal epithelium is maintained and what 

leads to damage is critical to broadening knowledge about 

inflammatory bowel diseases and developing prevention 

and treatment strategies. 

In this study, scientists explored how the intestinal 

epithelium promotes production of Th17 cells—immune 

system cells that produce a protein called IL-17 and 

Newly found connections between the nervous 

system and intestinal cells can control mucus 

production in the gut, helping to maintain the 

intestinal barrier and digestive health.

Scientists discovered a link between cellular 

stress and production of a type of immune cell 

implicated in development of inflammatory 

bowel diseases.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 59

contribute to both the protective barrier of the intestinal 

epithelium and to chronic inflammatory conditions. 

Th17 cell production is triggered by microbes adhering 

to the epithelium, but it is unclear how the epithelium 

orchestrates this response. Knowing that epithelial cells 

are susceptible to a cellular state known as endoplasmic 

reticulum (ER) stress, where the capacity of a cell to 

properly shape newly generated proteins becomes 

overwhelmed, they sought to determine if ER stress in 

the intestinal epithelium influenced production of Th17 

cells. To do so, they utilized two mouse models of ER 

stress and found an increased number of Th17 cells in 

both models. Interestingly, this increase in Th17 cells 

occurred in the mouse model even in the absence of gut 

microbes. This suggests that ER stress is a key player in 

Th17 production, and that, in wild-type mice, microbes 

may boost Th17 cell production by invoking ER stress 

in the epithelium. Additional experiments revealed 

that this response required production of a family of 

molecules called purine metabolites, most notably the 

small molecule xanthine. 

To explore whether ER stress was linked to Th17 

cell production in humans, the researchers looked 

at genes with increased activity in biosamples from 

people with ulcerative colitis and people with Crohn’s 

disease. They noted that Th17-, ER stress-, and purine 

metabolism-associated genes were increased in the 

samples, suggesting that the response observed in mice 

is also associated with inflammatory bowel diseases 

in humans. These studies revealed how ER stress in 

the mouse intestinal epithelium leads to increased 

production of Th17 cells, generating new knowledge of 

intestinal epithelium biology. Additional research will be 

needed to elucidate what causes Th17 cells to promote 

chronic inflammation and lead to the development of 

inflammatory bowel diseases.

Duan J, Matute JD, Unger LW,...Blumberg RS. Endoplasmic reticulum 

stress in the intestinal epithelium initiates purine metabolite synthesis and 

promotes Th17 cell differentiation in the gut. Immunity 56: 1115-1131.

e9, 2023. 

The Complex Interplay of Diet and the Gut Microbiome 

Influences Human Health: In a controlled feeding study 

in people, researchers found that a diet designed to 

nourish the gut microbiome led to altered microbial 

composition, diversity, and function; changes in people’s 

hormones; and improved energy balance (i.e., the relation 

of calorie intake to calories used or excreted). Gut 

microbes have long been associated with body weight 

and metabolism through their ability to harvest energy 

from food. However, prior studies in people have lacked 

the precision necessary for a comprehensive evaluation 

of the contributions of the gut microbiome to energy 

balance. Thus, in this randomized study, the researchers 

developed a diet intervention to address these critical 

knowledge gaps. 

Employing a microbiome enhancer diet (MBD) designed 

to deliver more fiber and other dietary sustenance to 

the gut, the researchers gave 17 healthy, weight-stable 

men and women either the MBD or a standard, Western 

diet (WD) with less fiber and more processed foods for 

approximately 3 weeks. This was followed by the other 

diet for the same amount of time. Using specialized 

laboratory techniques in a metabolic ward, the 

researchers measured energy intake, energy expenditure, 

and energy output (fecal and urinary) in each participant 

on each diet and made “within-participant” comparisons. 

They found that, compared to the WD, the MBD led to 

an additional 116 calories lost in feces daily, meaning 

less energy available for the person to metabolize 

and improved energy balance. When they explored 

compositional and functional changes in the microbiome, 

they discovered that the MBD led to an altered diversity 

of microbes and to an increase in microbes with an ability 

to break down nutrients, such as fiber, more efficiently 

to produce beneficial molecules compared to the WD. 

In addition, the researchers uncovered a small, but 

measurable, decrease in body fat stores on the MBD. 

Lastly, the MBD was associated with a notable increase 

in circulating hormones that are known to promote a 

feeling of fullness.

Taken together, these results suggest that an intentional 

remodeling of the gut microbiome through provision of 

adequate dietary fiber and minimally processed foods 

can modulate human energy balance. Future research 

on the complex interplay of diet and the gut microbiome 

could lead to personalized nutrition approaches. 

Corbin KD, Carnero EA, Dirks B,...Smith SR. Host-diet-gut microbiome 

interactions influence human energy balance: a randomized clinical trial. 

Nat Commun 14: 3161, 2023.

UNDERSTANDING INFLAMMATORY BOWEL 

DISEASE

Uncovering Biological Links Between Stress and 

Inflammatory Bowel Disease Flare-Ups: Researchers 

have identified biological pathways that link stress to 

worsening inflammatory bowel disease (IBD) symptoms, 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 60

suggesting that strategies to reduce stress could be 

an important component of IBD treatment. IBD, such 

as Crohn’s disease and ulcerative colitis, is marked 

by chronic inflammation in the intestines that causes 

debilitating symptoms. Stress is known to significantly 

impact inflammatory processes in the body and has been 

associated with triggering IBD flare-ups. The biological 

processes that link stress to the severity of IBD flare-ups, 

however, are not well understood. 

In new research, scientists found that stress 

exacerbated intestinal inflammation in different IBD 

mouse models. Comparing immune cells from colon 

tissue of stressed and control mice with IBD, the 

scientists found that stressed mice had higher levels of 

monocytes (a type of white blood cell) that promoted 

inflammation. The scientists next asked: how are stress 

signals transmitted from the brain to the gut to cause 

accumulation of monocytes? Surprisingly, they found 

that glucocorticoids—steroid hormones historically 

associated with reducing inflammation—were critical for 

triggering the observed stress-induced gut inflammation. 

They found that the glucocorticoids have two effects 

on the enteric nervous system (ENS, the gut's nervous 

system). First, they activate inflammatory pathways in 

a subset of glial cells in the ENS. (Glia and neurons are 

the two main cell types in the ENS.) The glial cells in 

turn recruit monocytes to the gut, thereby exacerbating 

inflammation in the colon. Second, glucocorticoids result 

in more undifferentiated, or immature, neurons in the 

ENS. The larger proportion of undifferentiated neurons 

means there are less of the signals (neurotransmitters) 

that mature neurons release, resulting in abnormal 

intestinal motility (movement of content through the 

gut). Finally, by studying three different cohorts of 

people with IBD, the scientists found evidence that these 

pathways likely played a role in mediating the effect of 

stress on IBD flare-ups in people. 

This study sheds light on underlying mechanisms that 

link stress to IBD flare-ups, identifying a key role for 

glucocorticoids interacting with glia in the ENS to 

increase the susceptibility of the gut to inflammatory 

triggers. It also suggests the importance of considering 

people’s mental health in the clinical management of 

IBD. Furthermore, the knowledge gained from this 

research may not only benefit people with IBD, but also 

those with other gut inflammatory diseases and other 

diseases that are worsened by stress.

Schneider KM, Blank N, Alvarez Y,...Thaiss CA. The enteric nervous system 

relays psychological stress to intestinal inflammation. Cell 186: 2823-

2838.e20, 2023. 

Expanded Study Diversity Uncovers New Genetic 

Risk Factors for Inflammatory Bowel Disease: 

Researchers recently identified new genetic risk factors 

for inflammatory bowel disease (IBD) by analyzing the 

genomes of tens of thousands of people from countries 

in East Asia alongside the genomes of people with 

ancestry from European countries. The inclusion of 

people from East Asia significantly expands the diversity 

of IBD genetic studies and provides insights that will help 

to understand and predict the disease.

Finding effective treatments for IBD, an umbrella term for 

Crohn’s disease and ulcerative colitis, has been challenging 

because it arises from a complicated interaction between 

genetic and environmental factors, resulting in a disease 

that varies from person to person. Researchers in 

the International IBD Genetics Consortium, of which 

NIDDK’s IBD Genetics Consortium is a member, have 

been combing through the human genome to find genetic 

variations (variations in DNA) that increase risk of IBD. By 

2022, genetic variations associated with IBD risk had been 

identified in close to 250 regions of the genome, providing 

insight into the biology of IBD and opening the door 

to the development of new treatments. Most of these 

studies, however, had been with participants from (or with 

ancestry primarily from) European countries, which limited 

genetic diversity and likely missed many genetic variations 

that could play important roles in IBD. (While everyone 

shares the same genes, and many genetic variations are 

also shared across ancestries, some genetic variations are 

more common in specific ancestries than others.) 

Recently, researchers expanded the diversity of IBD 

genetics research by analyzing the genomes of close to 

30,000 men and women from China, Japan, and Korea, 

including people with and without IBD, undertaking 

the largest IBD genetic analysis of participants from 

countries in East Asia to date. When the East Asian 

data were analyzed together with previous studies that 

included about 370,000 participants with ancestry from 

European countries, also including people with and 

without IBD, the researchers identified 81 new regions 

Researchers have identified biological pathways 

that link stress to worsening inflammatory 

bowel disease (IBD) symptoms, suggesting 

that strategies to reduce stress could be an 

important component of IBD treatment.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 61

of the genome associated with the disease, raising the 

total number of IBD-associated regions to 320. The 

researchers found that, in general, the amount of IBD 

risk contributed by genetics was similar between the 

East Asian and European populations; however, the 

genetic risk for Crohn’s disease was more influenced 

by ancestry than that for ulcerative colitis. They also 

tested whether the combined East Asian and European 

data would enable a more accurate prediction of IBD 

risk than the European data alone. Looking at IBD 

risk in Chinese individuals, the researchers found that 

the new data improved risk prediction significantly, 

underscoring the importance of including diverse 

study participants to improve ways of predicting the 

probability that any given individual might develop IBD. 

In addition to improving risk prediction, increasing 

the diversity of participants in IBD genetic studies 

also deepened the understanding of IBD by enabling 

identification of specific genetic variations that could 

drive the disease in all people. NIDDK’s IBD Genetics 

Consortium is currently expanding the diversity of its 

cohorts further; additional studies could determine exactly 

how genetic variations may affect IBD development across 

individuals and whether they could potentially serve as 

targets for new IBD therapies.

Liu Z, Liu R, Gao H,...Huang H. Genetic architecture of the inflammatory 

bowel diseases across East Asian and European ancestries. Nat Genet 55: 

796-806, 2023.

IMPACTS OF PANCREATITIS PAIN

Pain Linked to Lower Physical and Mental Health in 

People With Chronic Pancreatitis: Researchers have 

shown that people who experience severe or constant 

abdominal pain due to chronic pancreatitis also have 

significant loss of physical and mental health, suggesting 

that they may benefit from ways to detect and manage 

pain-related conditions.

While researchers continue to search for effective ways 

to treat—and ultimately cure—chronic pancreatitis, other 

important efforts have focused on ways to manage the 

most commonly reported symptom: pain, which can be 

debilitating. In other chronic diseases, pain has been 

shown to affect several aspects of health, causing anxiety 

and depression, for example. Knowing the effects of pain 

on the quality of life for people with chronic pancreatitis 

is important because it could guide treatment approaches 

that would help manage the disease.

To determine how pain might shape the lives of people with 

chronic pancreatitis, researchers gathered information from 

men and women (488 with pancreatitis and 254 without) 

participating in the Prospective Evaluation of Chronic 

Pancreatitis for Epidemiologic and Translational Studies 

(PROCEED). PROCEED is one of many clinical studies 

being conducted by the NIDDK- and NCI-sponsored 

Consortium for the Study of Chronic Pancreatitis, Diabetes, 

and Pancreatic Cancer, and is the first study in the 

United States to track chronic pancreatitis symptoms and 

progression in people over time. The researchers used a 

state-of-the-art assessment system for self-reported health 

called PROMIS (Patient-Reported Outcomes Measurement 

Information Systems), which was developed previously with 

NIH support. This assessment consists of questionnaires 

that provide highly reliable, precise measures of selfreported pain, along with measures of physical, mental, 

and social well-being. Applying PROMIS, the researchers 

found that the pain from chronic pancreatitis varies from 

person to person, ranging from no pain to severe pain, 

and from intermittent to constant pain. Most study 

participants, however, reported pain that was severe or 

constant, resulting in lower scores for overall physical and 

mental health. Severe or constant pain was also linked 

to declines in several specific health-related quality of life 

areas, including higher anxiety, depression, fatigue, and 

sleep disturbance. Participants with these categories of 

pain also had lower physical function, such as the inability 

to do everyday chores, and compromised ability to fulfill 

social roles. 

This study provides strong evidence that, in addition to 

the life-threatening organ and tissue damage caused 

by chronic pancreatitis, the associated pain can have 

profound effects upon an individual’s mental and physical 

well-being. This suggests that people with chronic 

pancreatitis may benefit from additional screening and 

treatment to manage pain and pain-related conditions.

Yadav D, Askew RL, Palermo T,...Conwell DL; on behalf of the Consortium for 

the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC). 

Association of chronic pancreatitis pain features with physical, mental, and 

social health. Clin Gastroenterol Hepatol 21: 1781-1791, 2023.

By analyzing the genomes of tens of thousands 

of people from regions in East Asia, researchers 

identified new risk factors for inflammatory 

bowel disease (IBD), helping to understand and 

predict the disease.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 62

PREVENTING AND TREATING 

LIVER DISEASE

Limits on Acetaminophen in Acetaminophen-Opioid 

Combination Medications Affected Causes of Acute 

Liver Failure: Researchers found that a U.S. Food 

and Drug Administration (FDA) mandate limiting the 

amount of acetaminophen in combination opioidacetaminophen pain relievers was associated with lower 

rates of acetaminophen and opioid-induced liver failure, 

although rates of liver failure from acetaminophen 

alone increased. The harms stemming from the 

opioid addiction crisis in the United States are well 

recognized, but pain relievers used in combination with 

(or instead of) opioids can also present safety hazards. 

Acetaminophen (or paracetamol) is a pain reliever and 

fever reducer commonly available over the counter and 

in prescription formulations combined with opioids. 

However, too much acetaminophen can cause liver injury 

or failure, and consumers can unintentionally ingest 

a dangerously high dose, especially if taking multiple 

acetaminophen-containing medications together. 

Combination acetaminophen-opioid medications can 

provide pain relief with lower doses of the two drugs, 

but previous research found that these combination 

medications might contribute disproportionately to 

acetaminophen overdoses. In January 2011, the FDA 

mandated that by March 2014 prescription combination 

acetaminophen-opioid products could only contain up 

to 325 mg of acetaminophen, reduced from the previous 

maximum of 750 mg. Manufacturers were also required 

to add a warning about the risk of liver injury to these 

medications’ labels. (This mandate did not affect overthe-counter acetaminophen products.)

To study the potential effects of this change, researchers 

used two large independent data sources, one on 

hospitalizations in the United States and the other on 

men and women with acute liver failure. By comparing 

hospitalization and acute liver failure rates, scientists 

concluded that after the FDA mandate went into 

effect, there was a significant reduction in the rate 

of hospitalizations associated with a combination of 

both acetaminophen and opioids, and in the rate of 

acute liver failure associated with this combination of 

medications. However, the rate of acute liver failure 

attributed to acetaminophen alone increased in the 

same time frame. Thus, the FDA rule on limiting the 

acetaminophen dose in combination acetaminophen and 

opioid preparations correlated with a decrease in the 

rate of acute liver failure and hospitalization associated 

with these medications. More research will be required 

to determine if this specific reduction in acetaminophen 

dosages caused these changes or if they were due to 

other factors, such as changes in labeling, prescribing 

patterns, or usage of either opioids or acetaminophen 

alone. Overall, these results illustrate the complexities 

of how acetaminophen is used and of balancing pain 

management and drug safety in real-world situations. 

Orandi BJ, McLeod MC, MacLennan PA,...Locke JE; US Acute Liver Failure 

Study Group. Association of FDA mandate limiting acetaminophen 

(paracetamol) in prescription combination opioid products and subsequent 

hospitalizations and acute liver failure. JAMA 329: 735-744, 2023.

Disrupting “Talk” Amongst Liver Cells Yields 

Therapeutic Targets for Nonalcoholic Fatty Liver 

Disease: Researchers “listening in” on how liver cells 

chemically “talk” amongst themselves have uncovered 

a host of new targets for therapies against a common 

and advanced stage of nonalcoholic fatty liver disease. 

Nonalcoholic fatty liver disease and its more severe form 

of nonalcoholic steatohepatitis (NASH) are common in 

both adults and children in the United States and around 

the world. No approved therapy exists for NASH, which 

is among the leading causes of liver transplantation and 

liver cancer. NASH is marked not only by excess fat 

accumulation in the liver, but also by liver inflammation 

and fibrosis, or scar tissue formation, mostly driven by 

overactivity of a type of liver cell called a hepatic stellate 

cell (HSC). Mechanisms driving this activation, or how to 

halt or even reverse it, are not fully understood. 

One potential way HSCs can become activated is by 

talking amongst themselves and with other cells nearby. 

As part of this “conversation,” the activated HSCs also 

send their own signals, creating self-perpetuating 

feedback loops or circuits. Scientists wondered if, 

by zeroing in on these signaling circuits, they could 

interrupt them, breaking the cycle that keeps the liver 

cells activated and causes disease. They used a new 

technology capable of analyzing genetic products of 

single cells—simultaneously for millions of cells—to 

provide a unique signature for each cell based on its 

signaling components. Examining liver samples from 

women and men with NASH and from male and female 

mice with diet- and chemical-induced NASH, they 

identified some common circuits, composed of 68 

unique proteins and their receptors, that emerge in the 

activated liver cells only during the late stage of NASH. 

The researchers then visualized these circuits using 

technologies that map contacts among neighboring 

cells. In this way, they showed the liver cells physically 

reaching out and becoming increasingly well-connected 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 63

to each other over the disease course, enabling exchange 

of short-range signals to sustain their collective 

activation and drive disease progression. To explore the 

therapeutic applications of this finding, the team blocked 

one of the protein-receptor signaling circuits in cultured 

human liver cells and in the animal model and found that 

blocking this circuit led to inactivation of disease-causing 

liver cells. 

In this study, the research team applied cutting-edge 

technologies in single-cell sequencing and imaging to 

uncover new insights into how to interrupt the “vicious 

cycle” of cellular signals underlying fibrosis in late-stage 

nonalcoholic fatty liver disease. This work offers a basis 

for developing what could be the first dedicated therapy 

for this common and severe form of liver disease.

Wang S, Li K, Pickholz E,...Friedman SL. An autocrine signaling circuit 

in hepatic stellate cells underlies advanced fibrosis in nonalcoholic 

steatohepatitis. Sci Transl Med 15: eadd3949, 2023.

Optimizing Treatment Regimens for Adults 

With Chronic Hepatitis B: In adults with chronic 

hepatitis B participating in NIDDK-funded Hepatitis 

B Research Network (HBRN) studies across 

North America, investigators tested whether a 

combination treatment regimen could increase 

long-term clearance of the virus. Chronic hepatitis 

B, a form of viral hepatitis, is a global problem 

that disproportionately affects people living in or 

originating from certain geographic areas, such as 

Asia and sub-Saharan Africa. If not appropriately 

treated, the disease can lead to cirrhosis, liver failure, 

and liver cancer. Effective treatments for chronic 

hepatitis B include interferon-based therapy, which 

targets immune cell function, and a class of drugs 

called nucleoside analogues that inhibit viral enzyme 

activity. However, these drugs’ effectiveness varies 

across individuals, in terms of reliably clearing the 

virus and ultimately preventing development of 

severe liver disease. In addition, these drugs often 

must be taken lifelong to prevent recurrence of 

disease; therefore, better treatments that clear the 

virus long-term are needed. 

The NIDDK-funded HBRN conducted clinical trials 

of treatment approaches for chronic hepatitis B in a 

study population that was primarily men, women, and 

children of Asian descent. Though the Network studies 

concluded in 2022, data analysis and publication of 

results have continued, with study samples available 

for additional research through the NIDDK Central 

Repository. One HBRN clinical trial in adults, results 

of which were recently published, assessed the safety 

and efficacy of combining two treatments—a longlasting form of interferon called peginterferon and 

the nucleoside analogue tenofovir—to increase the 

currently low or variable rates of viral clearance. Two 

hundred people with hepatitis B were treated, all 

of whom had active disease with high levels of viral 

DNA and elevations in serum liver enzymes, which 

indicate liver inflammation or disease. Half of the study 

participants’ samples contained the hepatitis B e antigen 

(HBeAg), a protein produced by the hepatitis B virus 

that signals an active infection. All study participants 

were treated with tenofovir for approximately 4 years; 

half also received peginterferon, but only for the first 

6 months. After 4 years, those individuals who had 

received combination therapy had a higher rate of 

clearing the viral proteins and viral DNA, though nearly 

all study participants had an excellent clinical and 

biochemical response. An overall complete response 

with clearance of all hepatitis B proteins, however, 

was uncommon. Furthermore, almost all responses 

occurred in people with HBeAg and a single type of 

hepatitis B virus called genotype A2, found mostly in 

White and Black populations and rarely among those of 

Asian ancestry. At the 4-year point, study participants 

were eligible to continue or to stop tenofovir therapy, 

based on withdrawal of therapy being one approach 

to increasing the rate of complete viral clearance. One 

year after withdrawal of tenofovir therapy, slightly 

more of the participants who stopped treatment had 

complete clearance than those who continued therapy. 

Furthermore, a proportion of the study participants 

who elected to withdraw from further tenofovir therapy 

had a severe flare of hepatitis and had to be restarted 

on treatment. 

These results indicate that the addition of peginterferon 

to tenofovir therapy for hepatitis B leads to an increased 

rate of response, but only in people with the viral 

protein HBeAg. Withdrawal of therapy after 4 years 

did not seem to increase the rate of complete response 

and could be followed by worsening of the hepatitis, 

requiring restarting of therapy. Future studies will 

continue to build on these findings to develop more 

effective, individualized approaches to treating people 

with hepatitis B.

Terrault NA, Lok AS, Wahed AS,...Janssen HLA; for the Hepatitis B Research 

Network. Randomized trial of tenofovir with or without peginterferon 

alfa followed by protocolized treatment withdrawal in adults with chronic 

hepatitis B. Am J Gastroenterol 118: 1214-1225, 2022.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 64

CONNECTING THE MICROBIOME AND 

LIVER DISEASES

Complex Interplay Among Gut, Liver, and Microbes 

Underlies Metabolic Changes in Chronic Hepatitis C:

A team including researchers from NIDDK’s Intramural 

Research Program uncovered how complex metabolic 

changes in the gut, its microbes, and the liver mirror the 

state of diseases such as chronic hepatitis C, which could 

lead to the development of new treatments for liver 

disease. The gut, the microbes it houses, and the liver all 

play central roles in the body’s metabolism of nutrients 

and their by-products. Nutrients and microbial products 

absorbed in the gut travel directly to the liver through 

the portal vein before they are further metabolized and 

distributed throughout the body. Liver disease, such as 

that resulting from chronic infection with the hepatitis C 

virus, not only damages the liver through inflammation 

and fibrosis (scar tissue formation), termed cirrhosis in 

severe cases, but also disrupts metabolic processing by 

human cells and microbes. 

Scientists selected chronic hepatitis C as a disease 

model in which to study how these complex metabolic 

and microbial changes correlate with the degree of 

liver disease. They recruited 23 men and women with 

chronic hepatitis C, either with or without cirrhosis 

present, to participate in a study at the NIH Clinical 

Center. Assessments included measures of human- and 

microbe-produced metabolites in blood samples from 

the portal vein and arm, liver biopsies, and fecal samples, 

taken initially and then 6 months after treatment with 

antiviral drugs to eliminate the viral infection. Over 

time, they found an anticipated uptick in immune 

activity and inflammation in these individuals, but also 

dampened gut-liver metabolism, particularly in utilizing 

fat for energy. Within the liver, these metabolic changes 

were localized to cellular structures called peroxisomes 

and mitochondria that handle inflammation-fighting 

antioxidants and energy production, and the changes 

persisted in cases of severe liver fibrosis even after 

the viral infection was cleared. Gut microbial activity 

was also altered with worsening liver disease, as 

microbes boosted fat production, reduced methane 

metabolism, and degraded the protective mucus lining 

the intestine, changing the mix of metabolites feeding 

into the liver and leaving both organs more vulnerable to 

inflammation. 

These findings illustrate how the fates of gut and liver 

are intimately linked, and that multiple disruptions in 

cellular and microbial metabolism in these organs are 

associated with inflammation and disease severity in 

the setting of chronic liver disease, in this case due 

to hepatitis C infection. They offer clues for future 

exploration into disease processes and therapeutic 

remedies to counter these metabolic changes and slow 

disease progression.

Ali RO, Quinn GM, Umarova R,...Heller T. Longitudinal multi-omics analyses 

of the gut–liver axis reveals metabolic dysregulation in hepatitis C infection 

and cirrhosis. Nat Microbiol 8: 12–27, 2023.

The Yin and Yang of Microbial Influences on the Liver 

Disease Primary Sclerosing Cholangitis: Studies in an 

animal model of primary sclerosing cholangitis (PSC), 

and in samples from adults with the disease, reveal 

gut microbes’ vital role in both countering and fueling 

this form of chronic liver disease. PSC results from 

autoimmune-driven inflammation and fibrosis (scarring) 

that block the ducts that carry bile out of the liver. These 

blockages cause bile to accumulate, leading to further 

damage and possibly liver failure. Males are more likely 

to develop PSC, which often occurs together with other 

autoimmune conditions. Factors influencing disease 

development and progression are unclear, and available 

treatments are limited to surgeries to re-open the bile 

ducts. Past research in people with PSC suggested that 

gut microbes might play a role, though exactly which 

species were protective or detrimental was unknown. 

To probe this important question, scientists studied 

an animal model of PSC: male and female mice that 

were genetically altered to develop features of the 

disease. They raised some of the mice under germfree conditions and inoculated other mice with specific 

microbes, then tracked their overall survival, weight, 

liver enzymes and fibrosis, gut microbes, and genetic 

and metabolic products. Overall, the presence of gut 

microbes was beneficial—mice that had been raised in 

sterile conditions gained lower than normal amounts of 

weight as they grew and had elevated liver enzymes and 

bile, bile duct damage resembling PSC, and shortened 

lifespans, compared to similar mice with gut microbes. 

The fates of each group could be switched by changing 

their microbes—either by giving germ-free mice a fecal 

Researchers studying adults with chronic 

hepatitis C have uncovered how complex 

metabolic changes in the gut, its microbes, and 

the liver mirror disease state, offering clues to 

counteracting disease progression.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 65

microbial transplant from the other group, or by giving 

antibiotics to the mice with microbes. By studying 

these mice and the effects of different antibiotics, 

the researchers were able to identify bacteria that 

exerted protective or pathogenic effects. Bacteria 

in the Lachnospiraceae family protected against liver 

damage while those in the Escherichia genus promoted 

it. Relevance to human PSC was tested through analyses 

of the bacteria in stool samples from Norwegian and 

German studies of men and women with PSC. 

These human PSC samples supported the mouse 

findings, with the presence of Lachnospiraceae bacteria 

correlating with better disease outcomes and some 

Escherichia bacteria correlating with more severe 

disease. Antibiotic use in people with PSC also 

appeared to shift the balance of these bacteria toward 

species associated with worse disease. 

Results from this study of PSC help form the knowledge 

base needed to enable more individualized predictions 

of disease progression based on the balance of beneficial 

and harmful microbes present. These results may also 

inform the development of personalized, microbe-based 

approaches to therapy for this liver disease.

Awoniyi M, Wang J, Ngo B,...Sartor RB. Protective and aggressive bacterial 

subsets and metabolites modify hepatobiliary inflammation and fibrosis in a 

murine model of PSC. Gut 72: 671–685, 2023.

Studies on the chronic liver disease primary 

sclerosing cholangitis revealed how the balance 

of different gut microbes can both counter and 

fuel disease, knowledge that could lead to more 

individualized therapies.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 66

FEATURE

Research Aims to “Triumph” Against 

Childhood Liver Disease

The impacts of liver disease can be devastating for 

children and their families. NIDDK and its partners 

support a wide range of research on liver diseases 

that affect children, with studies focusing on the early 

identification of disease resulting from multiple causes, 

preservation of liver function, and development of 

new treatment options. Much of this work is initiated 

by individual investigators supported by NIDDK, but 

the Institute also funds large networks of researchers 

focusing on specific types of liver disease in children.

RARE LIVER AND BILIARY DISEASES 

Since 2008, NIDDK has sponsored studies through 

its Childhood Liver Disease Research Network 

(ChiLDReN). The Network’s goals are to facilitate 

the understanding of many rare biliary diseases in 

which the liver is damaged due to impaired bile flow 

in children, to discover new diagnostic and treatment 

options, and to help train the next generation of 

investigators specializing in pediatric liver diseases. 

ChiLDReN consists of sites across the United States 

and Canada, with additional support provided through 

partnerships with the Cystic Fibrosis Foundation 

and the Alpha-1 Foundation. The Network conducts 

studies on a variety of liver diseases affecting children, 

including Alagille syndrome, alpha-1-antitrypsin 

deficiency, biliary atresia, cystic fibrosis liver disease, 

progressive familial intrahepatic cholestasis, and 

others. Several important advances have come from 

the Network’s research, such as important insights 

into the genetics, pathogenesis, and treatment of 

biliary atresia and Alagille syndrome. For example, one 

Network study helped to provide the data necessary 

for the U.S. Food and Drug Administration to approve 

the first dedicated treatment for severe itching 

associated with Alagille syndrome in children.

Porphyrias are rare, often inherited diseases that can 

affect the liver and other organs from a young age. 

NIDDK has provided support for studies on porphyrias 

through the Porphyrias Consortium, part of NIH’s Rare 

Diseases Clinical Research Network. The Consortium 

is supported by NIDDK and NIH’s National Center for 

Advancing Translational Sciences. The Consortium’s 

studies aim to understand disease mechanisms 

and progression of multiple forms of porphyria and 

develop new approaches to diagnosis, treatment, and 

prevention, with children currently participating in 

some of these studies.

NONALCOHOLIC FATTY LIVER DISEASE

In addition, NIDDK has supported pediatric research 

on the relatively common disease of nonalcoholic 

fatty liver disease (NAFLD) and its more severe form 

of nonalcoholic steatohepatitis (NASH). For example, 

the Nonalcoholic Steatohepatitis Clinical Research 

Network conducts clinical studies of nonalcoholic 

fatty liver disease in children. Recent studies by the 

Network have linked genetic risk factors to outcomes 

in children with NAFLD that can inform clinical care, 

and the Network has partnered with pharmaceutical 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 67

FEATURE

companies and the Eunice Kennedy Shriver National 

Institute of Child Health and Human Development 

on clinical trials testing the safety and efficacy of new 

treatments for pediatric NAFLD. 

ACUTE LIVER FAILURE

Acute liver failure in children can result from damage 

due to viruses, metabolic disorders, drugs and toxins, 

or other causes. It is one of the most common reasons 

for children to need a liver transplant. The Institute 

has sponsored studies in children on severe liver injury 

caused by drugs, herbs, and dietary supplements 

through its Drug-Induced Liver Injury Network, 

which aims to develop better tools for diagnosis and 

prevention, and to enhance knowledge of disease 

processes. Recently, Network investigators found 

that antimicrobial and anti-epileptic drugs are leading 

causes of this form of liver injury in children, which can 

lead to acute liver failure requiring a liver transplant. 

The newest of NIDDK’s pediatric liver disease research 

initiatives is also geared toward aiding children with 

acute liver failure. Launched in 2021, the Treatment 

for Immune Mediated Pathophysiology, or TRIUMPH 

study, is testing immunosuppressive therapy for 

children with acute liver failure of unknown cause. 

NIDDK has supported past studies on this topic 

through the Pediatric Acute Liver Failure Study Group, 

which paved the way for efforts such as TRIUMPH. 

The goal of the current study, which is currently 

enrolling participants at 20 sites across the country, 

is to test the safety and efficacy of two different 

treatments for improving survival of children with 

the rare and potentially life-threatening condition of 

acute liver failure for which no cause can be identified. 

Recent research supports the theory that many of 

these patients have liver injury related to heightened 

inflammation caused by an immune response to 

everyday infections or environmental exposures. 

Treatments to reduce inflammation may improve 

recovery in children with acute liver failure linked to 

immune disorders, increasing their chance of surviving 

and avoiding a liver transplant.

LIVER TRANSPLANT

Related to this work, NIDDK supports the Improving 

Medication Adherence in Adolescents who Had a 

Liver Transplant Network (iMALT) study, which is 

testing an intervention in young people who have had 

a liver transplant due to multiple causes, including 

liver diseases and acute liver failure. The study 

involves monitoring of blood medication levels and 

remote communications from study staff, in order to 

boost adherence to taking the immunosuppressive 

medications needed to prevent rejection of the 

transplanted organ. 

Through the collective efforts of these multi-center 

networks and investigator-initiated studies, NIDDK 

aims to help children and their families “triumph” over 

liver disease.

For additional information on the ChiLDReN and 

TRIUMPH studies see: childrennetwork.org/ClinicalStudies and www.pedsalf.com.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 68

FEATURE

Making New Connections to 

Address the Silent Epidemic of 

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease, or NAFLD, is one of 

the most common and growing types of chronic liver 

disease in adults and children, marked by excess fat 

storage in the liver. An estimated quarter of people in 

the United States have NAFLD, and up to 70 percent 

of people with type 2 diabetes also have NAFLD, 

though it often goes undetected. The disease often 

accompanies obesity and type 2 diabetes as part of 

a cluster of conditions called metabolic syndrome, 

though NAFLD can occur even in people who are 

lean and do not have diabetes, including those who 

carry some genetic factors and/or whose ancestors 

are from regions of the world with higher risk. Its 

more severe form of nonalcoholic steatohepatitis, or 

NASH, includes additional features of inflammation 

and scarring (fibrosis) that can lead, over many years, 

to compromised liver function; permanent damage, 

termed cirrhosis; liver cancer; and liver failure requiring 

a transplantation. There are currently no dedicated 

therapies approved by the U.S. Food and Drug 

Administration (FDA) for NAFLD and NASH. The 

current standard of care is weight loss through diet and 

exercise, which is challenging to achieve. Additionally, 

diagnosing these diseases is difficult because it relies on 

an invasive liver biopsy. New approaches are needed 

to prevent and treat NAFLD and NASH and to develop 

noninvasive means to identify people who could benefit 

from therapies as they become available. 

NIDDK supports a long-standing, multifaceted, and highly 

collaborative research program to improve understanding 

of NAFLD/NASH disease processes and identify new 

treatment approaches. The progress achieved through 

these efforts is made possible through the collective 

efforts of research teams and study participants at 

institutions across the country, at NIH, and internationally. 

EARLY STUDIES OF DISEASE 

DEVELOPMENT 

NIDDK sponsored early research on NAFLD and 

NASH to identify the biologic processes involved 

and chart the course of disease development and 

progression. In the 1990s, studies of liver biopsies 

from patients with obesity (with or without diabetes) 

identified some of the key morphologic changes 

that take place in NASH. They also tracked disease 

progression in these patients, some of whom 

developed fibrosis, which can progress to cirrhosis. 

Furthermore, these studies pointed to a link between 

NASH and insulin resistance, a condition that is also 

associated with type 2 diabetes. Additional studies 

in the early 2000s confirmed the link between NASH 

and insulin resistance, as well as other metabolic 

abnormalities, such as increased fatty acid breakdown 

and oxidative stress in the liver. NIDDK also 

sponsored population-level studies in the United 

States documenting the prevalence and risk factors 

for these diseases in people of different ages, genders, 

and ancestry. For example, disease risk at the time 

was found to be higher in people with ancestry from 

Hispanic and South Asian countries than in people 

with ancestry from African or European countries. 

CONNECTING RESEARCHERS TO 

ACCELERATE NEW APPROACHES

In 2002, NIDDK dramatically ramped up these efforts 

by establishing the NASH Clinical Research Network 

(NASH CRN), which supports a collaborative group 

of clinical researchers at centers across the country 

focusing on adult and pediatric forms of NAFLD 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 69

FEATURE

and NASH. Currently made up of teams and study 

participants at 17 participating clinical centers and a 

data coordinating center, the Network aims to advance 

understanding of disease causes and processes, 

and to also develop new approaches to diagnosing, 

treating, and managing these diseases. During the 

Network’s history, NIDDK has partnered with the 

National Cancer Institute and the Eunice Kennedy 

Shriver National Institute of Child Health and Human 

Development at NIH, and with the pharmaceutical 

industry, on clinical trials testing the safety and 

efficacy of new treatments for NAFLD/NASH. 

Over the past two decades, the Network has made 

many important contributions to the field, including 

developing a scoring system for diagnosing the disease 

and its progression, assessing genetic and other risk 

factors, and testing multiple candidate therapies. 

To date, the Network has enrolled thousands of 

adults and children who have participated in its many 

observational studies and clinical trials. These include 

trials showing that a daily dose of the natural form of 

vitamin E improved NASH in adult study participants 

and in some children. Network trials tested other 

possible therapeutic approaches, including the 

diabetes drug pioglitazone in non-diabetic adults 

with NASH and the kidney disease drug cysteamine 

bitartrate in children with NAFLD, both of which 

improved some features, but did not reduce overall 

disease. In 2015, Network investigators released 

results of a trial finding that a small molecule drug 

called obeticholic acid improved liver health in 

people with NASH, though the drug was associated 

with some increases in itching and total cholesterol. 

These findings helped fuel an explosion of industrysponsored NASH clinical trials of this drug and others. 

The NASH CRN collaborates with and complements 

industry partners by testing existing, low-cost 

agents that industry is unlikely to pursue, as well as 

conducting early phase studies of agents with novel 

mechanisms of action. 

Recent findings flowing from Network studies have 

shown a direct link between disease stage and 

outcomes in adults, with severe, later-stage disease 

associated not only with a higher risk of liver-related 

complications and death, but also with complications 

in other organ systems. And Network studies have 

uncovered new knowledge about the underlying 

biology of this disease, such as new genetic factors 

associated with responsiveness to vitamin E treatment 

in adults with NASH. Network research on genetic 

factors in children with NAFLD showed that some 

gene variants increase risk of the disease, particularly 

its more severe form. Because the majority of study 

participants were children with ancestry from Hispanic 

countries, these findings are particularly valuable for 

this at-risk population. These findings add to the 

evidence base for determining prognosis and informing 

clinical care for both adults and children with NAFLD.

The goal of the Network’s current phase is to continue 

database-driven studies of disease processes and to 

conduct new trials of NASH therapies for children and 

adults, with a constant emphasis on low-cost agents 

that could be implemented across the population. In 

recent years, a Network study found that the antihypertension drug losartan did not reduce signs of 

liver disease in children with NAFLD. Another study 

is determining the minimum effective dose of vitamin 

E in adults with NAFLD needed to improve liver 

enzyme levels. And the Network’s impacts are further 

amplified through availability of its databases and vast 

repository of samples for additional studies by other 

scientists. For example, a current ancillary study is 

characterizing and testing treatments for the disease 

in people living with HIV, a population in which 

NAFLD is projected to become the leading cause of 

liver disease. 

The Network also continues to develop and validate 

less invasive ways to diagnose NASH, such as by 

identifying biological markers of the disease and using 

imaging technologies. A recent ancillary study builds 

upon the NASH CRN to identify biomarkers in the 

blood that could be used in noninvasive tests related 

to NASH and NAFLD. Using data and samples from 

participants in four Network studies, the researchers 

provided evidence that these biomarkers could be 

used for noninvasive diagnosis of people at risk for 

NASH and for assessing the degree of fibrosis severity. 

This study was conducted through a collaborative 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 70

FEATURE

project called Noninvasive Biomarkers of Metabolic 

Liver Disease, or NIMBLE, overseen by the Foundation 

for the NIH with participation from the FDA, 

academia, and industry partners, with partial funding 

provided by NIDDK and NIH’s National Center for 

Advancing Translational Sciences. If approved by the 

FDA, these markers could be used instead of biopsies 

to more easily screen and diagnose people with 

NAFLD and NASH as early as possible in their disease 

course—an important milestone in clinical care.

INVESTIGATOR-GENERATED RESEARCH 

ADVANCES 

In addition to the highly productive NASH CRN, 

a wealth of investigator-initiated research efforts 

supported by NIDDK have made important, 

complementary contributions to advancing knowledge 

in this area. 

For example, NIDDK-sponsored investigators have 

performed clinical studies to identify genetic factors 

that could predispose some individuals to developing 

NAFLD. A 2008 study scanned the genomes of 

participants in a large population-based study to show 

that a variant in a gene called PNPLA3 was strongly 

associated with NAFLD and was more common among 

study participants of Hispanic ancestry with higher 

liver fat and inflammation. This was followed by a 

2010 study conducted by NIDDK scientists working 

at the NIH Clinical Center to further analyze genomic 

data from participants in the NASH CRN, as well as 

from people with NASH who participated in nonNetwork studies at the Clinical Center. This study 

found that the PNPLA3 variant was associated with 

earlier disease development in children. Other studies, 

including international ones, are identifying additional 

regions of the genome associated with NAFLD 

and are determining their functional significance 

as prospective treatment targets across diverse 

populations. 

Basic research in animal and cell models conducted 

by NIDDK-supported scientists has revealed new 

insights into disease development and possible 

treatment approaches. For example, a team of 

researchers supported by NIDDK and other NIH 

Institutes used mice and human liver cells to 

investigate how high amounts of fructose, a common 

ingredient in processed foods in the American diet, 

may promote NAFLD. They reported in 2020 that 

fructose can damage the intestinal barrier, which 

leads to inflammation and effects on the liver. Two 

teams of NIDDK-supported scientists tested lipid 

nanoparticles—used to deliver messenger RNA-based 

vaccines such as those developed against COVID-19—

in mouse models to improve delivery of treatments for 

liver fibrosis and NAFLD. Researchers “eavesdropping” 

on how liver cells chemically talk amongst themselves 

in animal and cell models uncovered a host of new 

potential therapeutic targets for advanced-stage 

NAFLD. NIDDK is supporting ongoing research 

to develop innovative models for fostering new 

discoveries, such as stem cells, genetically altered cells 

in culture, and three-dimensional organoids (“minilivers” grown in the lab) derived from people with 

NAFLD/NASH to develop personalized diagnostic 

biomarkers and treatments.

IMAGINING THE FUTURE OF NAFLD/

NASH TREATMENT: PAST PROGRESS 

FUELING NEW STRATEGIES

Recent years have witnessed the most rapid expansion 

yet of new treatment options under development for 

NAFLD and NASH. Many studies have focused on a 

new class of hormone-based drugs approved by the 

FDA for treating type 2 diabetes and obesity, such 

as semaglutide. These drugs work through a protein 

called the glucagon-like peptide 1 (GLP-1) receptor, 

and the development of these drugs stemmed from 

NIDDK-supported foundational research on GLP-1 

and related factors. This class of drugs causes delayed 

stomach emptying, reduced appetite, increased 

satiety, and enhanced insulin release and lower blood 

glucose levels, in addition to significant weight loss. 

In 2021, an industry-sponsored clinical trial featuring 

participation by NIDDK-supported scientists found 
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 71

FEATURE

that daily semaglutide treatment over a year and a 

half did improve disease resolution, based on the 

absence of inflammation or worsened liver fibrosis, but 

did not improve fibrosis stage in people with NASH 

but no cirrhosis. A 2023 study partially supported 

by NIDDK reported no improvement in disease, 

including resolution, in people with NASH and early 

cirrhosis who were treated weekly for a year with 

semaglutide, though the treatment did appear to 

be safe and have positive impacts on liver enzymes 

and liver fat. Researchers are conducting trials to 

determine whether longer-term treatment is required 

in people with cirrhosis resulting from NASH. NIDDKsupported researchers are currently conducting 

a clinical trial of semaglutide at the NIH Clinical 

Center in people with NAFLD/NASH to understand 

the mechanisms by which it may prove beneficial in 

treating the disease and identify predictors of clinical 

response. Additionally, NIDDK is supporting a new 

study testing another GLP-1 drug called liraglutide in 

young people with obesity, prediabetes or new onset 

type 2 diabetes, and NAFLD. And industry-sponsored 

trials are showing promising results in adults with 

obesity, type 2 diabetes, and fatty liver disease treated 

with similar drugs such as tirzepatide and testing other 

agents that target more than one receptor related to 

proteins like GLP-1.

Other novel treatment approaches are being 

investigated in parallel, including a study supported by 

NIDDK examining the impacts of intermittent fasting 

and aerobic exercise on NAFLD, which in combination 

were found to reduce liver fat more than either 

intervention alone. Another clinical trial is currently 

testing a low dose of the diabetes drug pioglitazone 

for improving signs of liver disease in people with both 

type 2 diabetes and NASH. NIDDK also supports 

many research projects overseen by industry scientists 

through the Small Business Innovation Research 

program that are testing new approaches to NAFLD/

NASH therapy.

ONGOING “NETWORKING” TO 

FACILITATE TREATMENTS

NIDDK continues to seek new opportunities to 

connect scientists studying NAFLD and catalyze 

research progress in this area, in addition to the 

ongoing NASH Clinical Research Network. In 2021, 

the Institute established the Liver Cirrhosis Network 

to conduct clinical and translational research toward 

expanding treatment options and transforming clinical 

care for cirrhosis caused by NAFLD and other forms 

of chronic liver disease. Network scientists are 

working in collaboration with a diverse population of 

adult study participants, some of whom have been 

underrepresented in past studies despite carrying 

a higher disease risk and burden. The Network is 

conducting an observational study, including on risk 

factors across racial and ethnic groups, to determine 

what drives cirrhosis progression and point to possible 

treatments. Current Network studies are also testing 

whether statins, which are drugs commonly taken 

for high cholesterol, can protect against cirrhosis 

progression. The goal of the Network’s studies is to 

usher in a new era of cirrhosis management, with a 

wider array of effective treatment options beyond liver 

transplantation, for NAFLD and other causes of severe 

liver disease.

For more information on NIDDK-sponsored research 

on NAFLD/NASH, such as the NASH Clinical Research 

Network, please see: www.niddk.nih.gov/healthinformation/liver-disease/nafld-nash/clinical-trials.

For more information on the NIDDK’s Liver Cirrhosis 

Network, please see: www.lcnstudy.org.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 72

Advancing Research to Improve the 

Health of People With Pancreatitis

People who have pancreatitis experience extreme, 

radiating pain caused by inflammation in the pancreas, 

a flat and oblong gland located behind the stomach. 

Aside from making hormones such as insulin needed 

to control blood sugar (glucose), the pancreas also 

performs another vital function: producing powerful 

enzymes for secretion into the small intestine, where 

they become activated and help break down food. 

But if these digestive enzymes are activated before 

leaving the pancreas—due to a blockage that prevents 

their flow into the intestine, for example—they can 

irritate or damage the pancreas, leading to painful 

inflammation that is often accompanied by other 

symptoms like nausea, vomiting, and fever.

THE VALUE OF RESEARCH

Pancreatitis is typically classified as acute (coming on 

suddenly and typically resolving over several days), or 

chronic (long-lasting), although there appears to be 

no clear boundary between these two types. Brief, 

acute episodes of pancreatitis can progress to the 

chronic form. It is possible, for example, to experience 

multiple unpredictable acute episodes (a condition 

called “recurrent acute pancreatitis”), stretching out 

the disease over years. Currently, there is no certain 

way to predict whether someone will progress from 

acute to chronic pancreatitis, which, if unchecked, 

can lead to serious life-threatening complications like 

kidney failure, breathing difficulty, and malnutrition. 

Additionally, the long-term inflammation and damage 

to the pancreas can impair insulin production, leading 

to diabetes. It also significantly raises the risk for 

pancreatic cancer.

There is no specific treatment for pancreatitis. 

The causes and course of the disease vary from 

person to person, making it difficult to find suitable 

targets for therapy. Several different factors can 

cause pancreatitis in different people; for example, 

some people have genetic variants that cause or 

contribute to the disease, though for many people 

with the disease, the cause remains unknown. (More 

information about pancreatitis is available on NIDDK’s 

website.) The search for treatments has also been 

hampered by the lack of large, long-term studies to 

understand the host of factors that influence how 

the disease develops and progresses. In addition, 

researchers have yet to identify early disease 

biomarkers—proteins or other chemicals in the body 

that could signal whether someone may eventually 

develop chronic pancreatitis. To address these needs, 

NIDDK, along with the National Cancer Institute 

(NCI), launched the Consortium for the Study of 

Chronic Pancreatitis, Diabetes, and Pancreatic Cancer 

in 2015. The Consortium’s goal is to design and 

conduct clinical studies to understand pancreatitis and 

its complications, including diabetes and pancreatic 

cancer. (See inset for the story of a participant in one 

of the Consortium’s studies.)

GAINING A BETTER UNDERSTANDING OF 

PANCREATITIS

Since its inception, the Consortium has overseen 

several major clinical studies. PROCEED (Prospective 

Evaluation of Chronic Pancreatitis for Epidemiologic 

and Translational Studies) has thus far enrolled close 

to 2,000 adult volunteers to understand disease 

progression, test potential biomarkers, and pave the 

way for clinical trials to test new therapies. Study 

participants are categorized into one of three groups: 

people with no pancreatic disease, people with 

suspected chronic pancreatitis (including those who 

have had one or more episodes of acute pancreatitis), 

and people with definite chronic pancreatitis. 

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 73

PERSONAL PERSPECTIVE

By collecting data and biological samples over time 

from all three groups, researchers can identify 

biomarkers and gain a better understanding of how 

pancreatitis progresses. For example, researchers 

in PROCEED recently found molecular markers 

in the immune system that are different between 

people with acute pancreatitis and people with the 

chronic form, suggesting these markers could serve 

as indicators for different stages of the disease. The 

researchers also identified inflammation signals that 

gradually increased as the disease progressed. These 

results provide a potential way to distinguish between 

someone experiencing pancreatitis or someone having 

unrelated abdominal pain. And, importantly, the study 

identified components of the immune system that 

could represent targets for new treatments.

Consortium researchers are also investigating 

complications that result from pancreatitis. Both 

chronic pancreatitis and pancreatic cancer could cause 

a form of diabetes called type 3c diabetes, which can 

be challenging to distinguish in the clinic from the 

more widespread type 2 diabetes. This is important 

because people with type 3c diabetes would likely 

require different treatment approaches from those 

with type 2 diabetes—they typically require insulin 

treatments earlier, for example. Recent results from 

the DETECT study (Evaluation of a Mixed Meal Test 

for Diagnosis and Characterization of Pancreatogenic 

Diabetes Secondary to Pancreatic Cancer and Chronic 

Pancreatitis) have found that, compared to people 

with type 2 diabetes, people with type 3c diabetes 

have lower levels of a substance called pancreatic 

polypeptide in their blood after consuming a test meal. 

This means measurement of pancreatic polypeptide 

levels could be used to differentiate type 3c from 

type 2 diabetes. Also, because type 3c diabetes 

often precedes other signs of pancreatic cancer, 

measurements such as this could potentially serve 

as tools to help detect pancreatic cancer in its early 

stages when treatment is more likely to be successful.

While both PROCEED and DETECT are studying 

pancreatitis in adults, the Consortium’s INSPPIRE 

2 study (International Study Group of Pediatric 

Pancreatitis: In Search for a Cure) is characterizing 

acute recurrent and chronic forms of pancreatitis 

in over 800 children and adolescents. (INSPPIRE 

2 is an expansion of INSPPIRE, an earlier pediatric 

pancreatitis study that predates the Consortium.) 

Similar to PROCEED, INSPPIRE 2 is gathering 

information from children with pancreatitis to help 

researchers determine the prevalence, causes, and 

progression of the disease. INSPPIRE 2 researchers 

have shown that the risk factors and course of the 

disease are different in children than in adults, a 

finding that could help researchers and clinicians 

develop better approaches to diagnose and treat 

children with pancreatitis. 

Along with these large clinical studies, the Consortium 

is continuing to engage in other research that focuses 

on the diagnosis and treatment of pancreatitis, 

including new ways to treat pain, with the goal 

of improving the lives of people living with the 

disease. The Consortium’s researchers—with the 

invaluable collaboration of the thousands of people 

participating in studies—are making great strides in 

understanding pancreatic disease, paving the way 

toward new treatments and bringing hope to those 

with pancreatitis. 

For additional information on the Consortium for the 

Study of Chronic Pancreatitis, Diabetes, and Pancreatic 

Cancer, please visit its website at: 

www.dmscro.org/cpdpc.
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 74

PERSONAL PERSPECTIVE

Dianna’s Story

On a winter night in Western Pennsylvania 20 

years ago, Dianna was at a friend’s house when her 

stomach suddenly began to hurt. Only a minute 

later, she was vomiting uncontrollably in the 

bathroom and experiencing the most excruciating 

abdominal pain she had ever felt in her life. Her 

friend’s mother drove her to a local emergency room, 

where she was told she had the flu. 

Looking back, Dianna, now a working mother of two 

in her mid-forties, knows the symptoms she had been 

experiencing were her first encounter with recurrent 

acute pancreatitis, which would continue to barrage her 

pancreas with repeated bouts of painful inflammation. 

But she had little reason to suspect she had the disease 

at the time—no one in her family had it, and she had 

no risk factors that she had been aware of. So, a week 

and a half after that emergency room visit and with the 

vomiting under control, she started her new job. She 

would still feel sore for weeks. “I just pushed through 

it,” she says with a casual grin and a shrug.

Dianna speaks with an entertaining, witty, and wry 

sense of humor. She has always been good at math 

and problem solving, talents she uses to design 

simulators—life-sized replicas of control stations that 

provide hands-on training for students. They have 

all the switches, gauges, and warning lights that the 

real equipment has. “You want [the students] to be 

trained so they know what to do when a component 

fails, and how to rectify it,” she says.

But pancreatitis episodes do not come with warning 

lights, and there is no way to prepare for the 

debilitating pain. If untreated, pancreatitis could 

lead to organ failure and death. “I get zero warning,” 

she says. “I could be talking to someone, and by the 

end of our conversation I could be on the way to the 

emergency room, because the pain comes sharp, and 

I just start vomiting... and off we go.”

CLOSE CALLS

In August of that same year when Dianna had her 

first episode, she was visiting her parents when, 

out of the blue, she began vomiting every hour 

Dianna is participating in the PROCEED study, which aims to better 

understand pancreatitis

“I get zero warning,” Dianna says of her 

pancreatitis attacks. “I could be talking to 

someone, and by the end of our conversation 

I could be on the way to the emergency room 

because the pain comes sharp, and I just 

start vomiting... and off we go.”
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 75

on the hour, like clockwork. Still unaware of her 

pancreatitis—and suspecting something less serious 

like the stomach flu—she decided to wait until the 

next day to see a doctor. The doctor immediately 

sent her to a hospital where she waited for 12 hours 

in a backed-up emergency room. She was severely 

dehydrated by the time she was admitted, and her 

kidneys were starting to fail. “They had no idea 

what was wrong,” she says. “They pulled my mother 

outside and told her I was dying.” 

Eventually the medical staff were able to stabilize her. 

She was diagnosed with pancreatitis and stayed in the 

hospital for 11 days while the doctors searched for a 

cause. An important clue had come in her bloodwork: 

it was normal except for her triglycerides, which were 

“sky-high,” she says. A healthy triglyceride level is 

under 150 milligrams per deciliter (mg/dL); Dianna’s 

would regularly be well over 1,000 mg/dL—and at 

times much higher.

Like so many aspects of the disease, the role 

triglycerides play in pancreatitis is not completely 

understood. One possibility is that high levels of 

triglycerides could cause the pancreas to overproduce digestive enzymes. The resulting buildup 

of these powerful enzymes in the pancreas could 

lead to permanent damage and other life-threatening 

complications—including a higher risk for pancreatic 

cancer—all the while causing painful inflammation in 

the abdomen. 

Dianna’s pancreatitis, she later learned, is caused by 

three genetic variations in her DNA: one that raises 

the overall risk of the disease and two that cause high 

triglycerides. Keeping her triglycerides lower has 

been a challenge. She tries to limit her diet to low-fat 

and low-carb foods, and some triglyceride-lowering 

medicines she’s taken had very serious side effects, 

including severe depression.

Dianna describes the pain caused by pancreatitis as 

like a very bad friction burn, but on the inside of the 

body, and it can last for weeks. “It becomes so severe 

that you just want to double over, and nothing you do 

makes it feel any better,” she says. Given the choice, 

she would prefer the pain from natural childbirth—

which she experienced when each of her two sons 

were born—over the pain from pancreatitis.

The August trip to the hospital was the first time 

Dianna came close to dying. The second came several 

years later. This time the hospital was full, and she 

was directed to a smaller hospital that struggled to 

get her symptoms under control. While she slipped 

into unconsciousness, “they worked feverishly to keep 

me alive,” she says. “As soon I was conscious again, 

they told my husband and me to say a last word to 

each other because they weren’t sure if they were 

going to pull me through.”

She remembers her husband refusing to say goodbye: 

“He said, ‘I’m not saying it, because you’re making it 

through this. Because we’re not done. This is not the 

end.’” With those words, she says, “he really gave me 

strength.”

The small hospital airlifted Dianna by helicopter to 

the University of Pittsburgh Medical Center (UPMC), 

where, luckily, she was able to recover. 

PROCEEDING THROUGH LIFE WITH 

PANCREATITIS

At UPMC, Dianna met Dr. Dhiraj Yadav, a 

gastroenterologist and investigator in NIDDK’s 

Consortium for the Study of Chronic Pancreatitis, 

Diabetes, and Pancreatic Cancer, who took her on 

as a patient. He also encouraged her to participate 

in one of the Consortium’s major research efforts, 

Prospective Evaluation of Chronic Pancreatitis 

for Epidemiologic and Translational Studies 

(PROCEED), which has thus far collected data on 

close to 2,000 volunteers to better understand 

pancreatitis. The study’s ultimate goals are to 

develop new therapeutic options and create 

tools to predict how the disease might progress 

in any individual, which would also help to guide 

treatment approaches.

PERSONAL PERSPECTIVE
NIDDK Recent Advances & Emerging Opportunities 2024: Digestive Diseases and Nutrition 76

Dianna says her participation in PROCEED is simple: 

it involves completing an annual questionnaire and 

giving blood and stool samples. “I found it easy,” 

she says. “And I feel like it’s a two-way thing. If 

something can be learned from me, maybe it’ll turn 

around and benefit me as well.” And, she says, 

one of her worst fears is that her sons may have 

inherited the disease. “So, even if it takes 10 years 

to figure out, maybe it’ll help my kids.”

Dianna’s harrowing experiences with pancreatitis 

attacks—she’s had 16 of them over the years—have 

given her a new perspective in life. Her motto 

has become “laugh, don’t cry,” partly because she 

always looks for the silver lining in bad situations, 

and partly because she spent a lot of time in the 

hospital connected to a feeding tube that went 

through her nose, which she says can be especially 

uncomfortable with stuffy sinuses from crying. (She 

likes to make hospital staff laugh by referring to the 

medical tubes clinging to her neck as “her jewelry.”) 

“There are times when crying is very much needed,” 

she says. “But if you can find something to laugh 

about first, no matter how small, then you can tap 

into that feeling of ‘Yes, I can do this!’”

Her friends share her sense of humor. Once, wishing 

they could give her a new, disease-free pancreas, 

they presented her with a stuffed plush version 

instead. “It’s those kinds of things that help,” Dianna 

says. “Laughter is the better medicine.” 

Still, she draws much of her resiliency from within. 

“Even though it can get depressing, and I’m spending 

a week or two in the hospital at a time, I bounce 

back,” she says. “I keep going.”

Says Dianna about the PROCEED 

study, which aims to better understand 

pancreatitis: “I feel like it’s a two-way 

thing. If something can be learned from me, 

maybe it’ll turn around and benefit me as 

well.”

“There are times when crying is very much 

needed,” Dianna says of her many hospital 

stays due to pancreatitis. “But if you can 

find something to laugh about first, no 

matter how small, then you can tap into 

that moment of ‘Yes, I can do this!’”

PERSONAL PERSPECTIVE