Cirrhosis Fueled by Environmental Factors, Mental Health Disorders
Liver cirrhosis, also known as the fourth and most advanced stage of fibrosis, can result from a variety of causes including nonalcoholic fatty liver disease and very often from alcohol-related liver disease — the lines of which can also be blurred.
While approximately 80 million people in the United States have some fat accumulation in their livers, the estimated number of individuals who have progressed to bridging fibrosis or cirrhosis is much lower at around 3 million. The incidence of cirrhosis and rates of death due to cirrhosis are increasing, however, due more now to diet and lifestyle choices than viral diseases.
Healio Gastroenterology and Liver Diseases spoke with several hepatologists on the changing trends in cirrhosis etiology that have followed increasing rates of obesity and excessive alcohol consumption to shed light on the behavioral links between lifestyle and late-stage liver disease.
“That question is at the core of the field of hepatology now, certainly for fatty liver disease,” Michael R. Charlton, MBBS, director of the Center for Liver Disease at the University of Chicago Medicine, told Healio Gastroenterology and Liver Disease. “While there are important genetic susceptibility factors that are being identified, there also are environmental things like nutrition and alcohol that can, over the course of a couple decades, lead to cirrhosis.”
Charlton explained that while the prevalence of advanced fibrosis in the U.S. may only be 1% in the general population, the percentage increases to over 7% in those with type 2 diabetes. Additionally, modeling studies have shown a projected 170% increase in rates of compensated cirrhosis and a 180% increase in liver-related deaths between 2015 and 2030.
“There have been remarkable shifts in causes of liver disease,” he said. “The big shift in cirrhosis etiology has been the decline in end-stage liver disease due to hepatitis C, and at the same time we’ve seen an increase in ESLD and liver-related deaths from alcohol and from nonalcoholic fatty liver disease. These two are occurring essentially in parallel and may interact with each other; it may be that you have NAFLD and you drink more than is healthy, which leads to a synergistic effect, accelerating fibrosis of the liver.”
The U.S. Preventive Services Task Force, which oversees broadly accepted guidelines for screening, has a set of criteria that must be met before screening for any complication is recommended. These elements include an FDA-approved therapy that has been shown to have a meaningful impact on outcomes, which is not currently true for NAFLD, NASH or cirrhosis.
“Obesity and metabolic syndrome go hand-in-hand and may promote progression of fibrosis,” Charlton said. “If you’re going to consider screening a population for fibrosis progression, it would be on a case-finding strategy that would include higher risk groups such as those with type 2 diabetes and medically-complicated obesity, who are much more enriched with advanced fibrosis.”
Charlton pointed to emerging noninvasive tests easily performed by physicians in general practice and specialists who are not hepatology-focused, such as the NAFLD Fibrosis Score and the Fibrosis-4 Index. These are noncommercial and readily available calculators that can be found online. The scores stratify patients in low, medium and high-risk categories for advanced fibrosis.
“With 80 million people with some fat in the liver, there is not even close to enough hepatologists to see them all,” he said. “Patients with noninvasive biomarker results in the low risk category don’t have advanced fibrosis more than 5% of the time so you’re right 95% of the time. The most important aspect of noninvasive biomarkers is that the likelihood of clinical events in patients with low risk profiles are incredibly low.”
Alcohol causes liver injury in multiple ways including but not limited to disrupting normal mitochondrial function, increasing the amount of fat deposition and inflammation in the liver, and disrupting the gut barrier, which results in more bacterial inflammation transmitted to the liver.
Elliot B. Tapper, MD, an assistant professor of gastroenterology at University of Michigan, highlighted that alcohol as the etiology for cirrhosis and cirrhosis-related deaths is rising among younger patients. While most individuals who die of cirrhosis tend to be aged 50 years or older, there has been a disproportionate rise in those who develop cirrhosis between age 25 years and 34 years, increasing by 200% since 2008.
Tapper continued to describe the three most likely causes for these changes. For one, younger people are more likely to binge drink; two, the actual concentration of alcohol in drinks has increased; and three, the increasing rates of obesity compound damage to the liver.
“It’s well known that one plus one equals three,” he said. “When you add alcohol to obesity, if fat is preexisting in the liver and you add the inflammatory insults of alcohol excess then you get much more rapid liver injury. If you want to understand why people today are more likely to get into trouble with their drinking, it’s pattern — what they’re consuming — and their comorbidities — mainly obesity.”
When assessing a patient with an unclear history of excessive alcohol use, Tapper suggested two routes. The first is to use biomarkers including ethyl glucuronide from a urine test and the blood biomarker phosphatidylethanol. These allow for quantification of continued alcohol use for approximately 1 week or between 4 weeks and 8 weeks, respectively.
Additionally, he suggested changing the question of “how much do you drink?” to “what do you drink?” and “how often do you go to the store to buy it?” as a technique to estimate quantity and frequency of drinking. Instead of a potentially rehearsed answer to the first question, the second question provides a framework to estimate quantity and frequency of alcohol consumption and is not what a patient may expect.
Tapper concluded that despite these alarming trends, there is a ray of hope.
“The truth is that alcohol-related liver disease offers us a golden opportunity because there are few other diseases that can be turned around like it,” he said, explaining that even patients with severe cirrhosis can usually expect improvements after cessation of drinking.
“Three to 6 months, that’s a good watershed,” he said. “It can be frustrating for a patient who has stopped drinking and maybe also improved their diet to not see changes in their ultrasound results or lab tests right away, but it’s a just a matter of time. If you stop drinking, you are going to get healthier.”
Diet, Mental Health
As Tapper had mentioned, alcohol is only one part of the equation of cirrhosis etiology. Charlton also added that while patients are well-aware that diet and exercise are good for them, it can be difficult to implement, and that obesity and poor nutrition are often undertreated. Mental health disorders such as depression and anxiety are often found in the same spheres as unhealthy eating habits and substance abuse. This presents an additional health care-related factor driving behaviors that in turn lead to liver injury.
“The most common mental health disorder that we find in patients with cirrhosis is depression,” Jasmohan S. Bajaj, MD, professor of medicine at Virginia Commonwealth University and researcher at the Maguire VA Center, told Healio Gastroenterology and Liver Disease. “Some cases may be mild depression, but depression has been associated with poor nutrition and with greater alcohol use which fuels the cirrhosis epidemic further.”
On the topic of improving diet for liver health, Bajaj pointed to his research experience with the “Mediterranean diet.” What he and colleagues found was that patients with cirrhosis from Turkey who predominantly had a lot of fermented milk products in their diet had lower risks for hospitalization that could not be explained alone by a lower MELD score.
“Larger studies in NAFLD with people who don’t have liver disease have shown that a Mediterranean diet, if followed properly, has liver health benefits and we wanted to actually expand that into patients with decompensated cirrhosis,” Bajaj said. “In other words, it’s never too late to change your diet. What we have found is that not only the constituents of the diet but also the resulting change in the microbiota diversity has effects on things such as amino acids and lipids that occur in the plasma that can modulate what occurs in the liver.”
Combining the aspects of alcohol misuse, dietary choices, and mental health disorders, Bajaj said that it was astounding the number of patients with cirrhosis who have never been asked if they have depression or alcohol use disorder, because physicians may be worried about what to do next if the answer is yes.
“Every clinic has to have a path ready if the patient says yes,” he said. “Some clinics may not have psychiatric services available, which may not be problematic as depression is usually covered by primary care, but recent data show the promise of using telemedicine services. The patient does not need to be at a specific location to receive a psychiatric evaluation. Just because you do not have a psychiatrist in office, does not mean you should not be able to explore these options. What we need to do as practitioners is to have a game plan ready if the answer is yes, because if the answer is yes and we have no actionable item at the end of it, patients may not be as forthcoming in the future.”
Jessica L. Mellinger, MD, an associate professor at University of Michigan, offered insight into how hepatology has become a behavioral specialty in recent years.
“We have seen alcohol abuse become a major behavior leading to a lot of admissions and readmissions. What I’ve been seeing is a lot of younger people and a lot of polysubstance abuse,” she said. “These are people who are not just abusing alcohol, they’re smoking, using marijuana or other drugs, and using opioids. This really increases the complexity of the patients we’re seeing in the hospital. Having comorbid substance use issues can make it more difficult to find adequate treatment regimens because they are so complicated, especially when they have advanced liver disease.”
Cirrhosis is silent and oftentimes is only diagnosed after a patient has reached out to a physician or required hospitalization for related complications such as ascites, jaundice, or hepatic encephalopathy, which is a type of confusion and delirium that can occur in advanced liver disease. The concern for many physicians once cirrhosis is identified is to avoid readmission and make sure that patients are able to understand the management of their disease.
“When we think about readmission, hepatic encephalopathy is a major risk factor for people coming back to the hospital,” Mellinger continued. “In many cases, the medication regimen is complicated. It can be difficult to understand how to take all these new medications and, added to that, their significant confusion from hepatic encephalopathy can make it tough to understand and remember instructions.”
One of the greatest assets to avoiding readmission is ensuring that a patient follows up with either a specialist or their primary care physician within the first month after hospitalization. Research has shown that patients who saw a physician within 4 weeks of first admission had lower rates of readmission.
“In many of those cases, I believe it was because the physician or health care provider was able to catch these issues with medication early, provide additional education, and make sure that medication administration was adhered to properly so that these patients don’t return to the hospital unless needed,” she explained.
With a spread of health-related concerns for chronic liver disease — diet, substance abuse, and mental health disorders — along with comorbidities such as diabetes and cardiovascular disease, hepatology experts have promoted the importance of multidisciplinary care and interdisciplinary plans of action for patients.
Mellinger spoke about her personal experience putting together different specialist teams.
“With general cirrhosis readmissions, having a team of people including nurses, pharmacists, primary care physicians and specialists make contact in between when patients with cirrhosis leave the hospital and when they have their next scheduled appointment can be very helpful. We’ve seen how powerful that type of coordinated communication can be here at Michigan,” she explained. “We have a post-discharge pharmacy review where our pharmacist will call patients with cirrhosis and perform a thorough medication review that goes through all the specific medications and new instructions. This all happens over the phone. Following this, the pharmacist sends us a note that describes the issues. Maybe the patient needs a medication adjusted or they need more education about their medication regimen. Our team can reach out to the patient and make changes before the patient winds up in the hospital again. This process has been very helpful in picking up these red flag issues to help avoid readmission. It’s a very patient-centered way to approach patient care and a great way to use a multidisciplinary team to make sure we keep patients out of the hospital if they don’t need to be here.”
Mellinger also helped develop an alcohol-related liver disease multidisciplinary clinic with a psychology specialist, a psychiatrist, a social worker, and a hepatology nurse to provide patients alcohol treatment and liver care in one location. This team has solved some of the problems in which a psychiatrist may not feel comfortable prescribing liver-related medications and where hepatologists are not comfortable prescribing psychiatric medications.
“Hepatologists are often uncomfortable prescribing anti-craving agents or psychiatric medications because we’re not addiction specialists, and patients with cirrhosis often need dose adjustment to these medications because of their liver disease. These patients can fall through the cracks and get suboptimal treatment for their alcohol-use disorders,” she explained. “That, as you might imagine, can lead to higher rates of relapse and more issues with readmission for liver disease-related issues if they continue to drink. Having mental health care integrated with hepatology care has allowed us to offer the full range of alcohol use and psychiatric treatment to our patients with alcohol-related liver disease. This is critical to improving long-term outcomes in this population.”
Multidisciplinary care should also involve the primary care physician, she noted, to ensure all lines of health care communication are clear.
“There are not even close to enough improvements in multidisciplinary care as of yet,” Charlton added on the topic. “What should be the cornerstone for an approach for patients with NAFLD is that these patients inevitably have other things going on. The great majority have medically-complicated obesity. We have in our practice an endocrinologist, which I think should be a prerequisite for a multidisciplinary fatty liver disease clinic. We have a hepatologist, a nutritionist, and then we employ point-of-care imaging with vibration-controlled transient elastography. Multidisciplinary teams should be an increasingly common way to manage and treat patients with NAFLD and cirrhosis.” – by Talitha Bennett
- Andresen-Streichert H, et al. Dtsch Arztebl Int. 2018;doi:10.3238/arztebl.2018.0309.
- Bajaj J, et al. Hepatol. 2017;doi:10.1002/hep.29791.
- Cox IJ, et al. Liver Int. 2019;doi:10.1111/liv.14256.
- Kim D, et al. Gastroenterol. 2018;doi:10.1053/j.gastro.2018.07.008.
- Tapper EB, et al. BMJ. 2018;doi:10.1136/bmj.2817.
- For more information:
- Jasmohan S. Bajaj, MD, can be reached at email@example.com.
- Michael R. Charlton, MBBS, can be reached at firstname.lastname@example.org.
- Jessica L. Mellinger, MD, can be reached at email@example.com.
- Elliot B. Tapper, MD, can be reached at firstname.lastname@example.org.
Disclosures: Bajaj, Mellinger and Tapper report no relevant financial disclosures. Charlton reports receiving consulting fees, research support or other financial benefits from Bristol-Myers Squibb, Conatus, Gilead, NGM-Bio and Novartis.