The first sign that there might be something wrong with Trish Zappone’s liver came in 1992, when she was 41. A routine blood test for a life insurance policy showed elevated liver enzymes, a red flag that can indicate inflammation of the liver. She consulted her primary care physician, who assured her that this is seen frequently, often considered to not be important, and not to worry.
Zappone went about her life, working in banking and income tax preparation, raising her son with her husband in their Prospect, CT, ranch home, and even marching in a drum corps. Fifteen years later, red spots appeared on her neck, shoulders, and face. Her doctor diagnosed rosacea, a common skin disorder.
When she visited her doctor a few months later for something else, she saw a different physician. Zappone asked about the spots, which had worsened. After examining Zappone’s chart and seeing the heightened enzyme levels from years past, the doctor asked, “You know you have liver disease, right?” Zappone recalls. Red or purplish spots can be a sign of cirrhosis, which is severe scarring of the liver.
Zappone underwent various tests and was referred to a gastroenterologist, who then sent her to a Yale Medicine liver specialist, where she was diagnosed with nonalcoholic steatohepatitis (NASH), a dangerous form of nonalcoholic fatty liver disease (NAFLD), in 2007.
NAFLD is a condition in which extra fat is stored in the liver. The most common kind is called fatty liver disease, which does not involve liver inflammation (hepatitis) or cell damage. NASH, the other type, is more serious because those who have it also have inflammation and liver cell damage, which can lead to progressive liver scarring over time and, eventually, cirrhosis.
In Zappone’s case, the prognosis was grim. The median survival rate for her advanced disease stage was two years—unless she had a liver transplant.
Why early diagnosis is important
Once NASH reaches an advanced stage, the only treatment is a transplant. That’s why it is important to catch it early, when only limited fibrosis, or scarring, of the liver is present, and can be reversed by weight loss and control of risk factors such as high blood sugar, high cholesterol, and blood pressure. If the scarring becomes permanent, the scar tissue will create bands throughout the liver that impair its basic functions and ability to regenerate. When this happens, a person is diagnosed with cirrhosis.
The problem, says AnnMarie Liapakis, MD, a Yale Medicine liver transplant specialist, is that this type of liver disease often develops without any symptoms in the early stages and is therefore frequently missed. If early clues, such as elevated liver enzymes or fat in the liver noted on abdominal imaging studies, aren’t noticed or acted upon, it’s a missed opportunity.
The exact causes of NAFLD—including fatty liver disease and NASH—are not known, but both types occur more commonly in people who are obese or have conditions such as type 2 diabetes. And as obesity rates continue to rise among adults in the U.S., so has NAFLD. Currently, up to 33% of the population has NAFLD and about 5 to 7% have NASH. Alcoholic liver disease and NASH recently unseated hepatitis C as the leading causes of advanced liver disease for those awaiting a liver transplant.
For Zappone’s part, by the time she reached Yale, her NASH had progressed to the point where she had both cirrhosis and portal hypertension—a common complication of NASH. It refers to abnormally high blood pressure in the portal vein, which is located in the right upper quadrant of the body and transports blood from the gastrointestinal tract, gallbladder, pancreas, and spleen to the liver. Almost all of the blood in the body passes through the liver, and two-thirds of this blood supply comes from the portal vein.
“When the liver is scarred, it is resistant to blood flowing through it—like a traffic jam in the portal vein,” Dr. Liapakis explains. “The blood backs up to the spleen, which becomes enlarged. So, the body tries to offload the pressure by creating new veins for the blood to bypass the high pressure in the liver. These veins in the food pipe or stomach can lead to internal bleeding, which may be life-threatening.”
This entire process can cause fluid to build up in the belly, as well as episodes of encephalopathy, a loss of brain function that occurs when the liver is not able to filter out toxins as it normally would.
The cirrhosis and portal hypertension made Zappone’s NASH diagnosis clear. Portal hypertension had caused 18 pounds of fluid buildup in her abdomen. She also experienced encephalopathy, along with seizures, confusion, and trouble speaking. She was hospitalized twice.
“The second time it happened, I went to bed on a Saturday night and woke up in the ICU on Monday,” she recalls.
Not always related to lifestyle
While the severity of Zappone’s condition was understood, her reasons for getting NASH were not as clear. Risk factors for NASH—and, in fact, NAFLD in general—include metabolic syndrome, which is defined as having at least three out of five risk factors: obesity, type 2 diabetes, pre-diabetes, high blood pressure, and high cholesterol.
Aside from often carrying 10 to 15 extra pounds of weight, Zappone didn’t have any of those risk factors. She was a regular exerciser, taking long walks every day. But, two other members of Zappone’s family have had NASH, and while the disease isn’t known to be hereditary, certain genes can predispose people to it, Dr. Liapakis says.
Plus, there is a form of NASH often referred to as “lean” or “low weight” NASH, which can arise in a patient who is not actually overweight, but is instead related to the way their weight is distributed. It’s thought that a lack of sufficient muscle mass may cause more fat storage in the liver, explains Wajahat Mehal, MD, PhD, director of the Metabolic Health & Weight Loss Program and a member of Yale New Haven Hospital’s Fatty Liver Disease Program.
For those patients whose NASH is related to weight, Dr. Mehal says the good news is that incremental weight loss can make a big difference. “You can lose 8 to 10% of your weight and your liver disease will improve,” he says. “For example, that might mean going from 240 pounds to 215, which is difficult, but not impossible.”
Drs. Mehal and Liapakis agree that everyone should know that if their blood tests show abnormal liver function, it’s important to pursue the reasons why. If your primary care doctor isn’t particularly concerned, ask whether you should see a liver specialist, or hepatologist, to pin down potential causes and help identify the right solution. “It’s not really something that primary care physicians are equipped to do,” explains Dr. Mehal, adding that they don’t always have the time or resources to fully investigate the liver issue.
And, if NASH advances to severe cirrhosis and portal hypertension, as it had with Zappone, weight loss won’t help. “If you diagnosis the disease early, you can intervene and prevent further progression,” Dr. Liapakis says. “If there is heavy scarring and high pressure [portal hypertension], it’s too far gone and a transplant will likely be required.”
A long wait for a transplant
For Zappone, transplant was the only remedy. In addition to working with Yale New Haven Hospital’s Liver Transplants Program and placing her name on the wait list with the Yale New Haven Transplantation Center, Zappone considered applying for transplant lists in the South, where she had greater odds of receiving an organ because of relatively greater availability of donor organs. But in the end, “I put all my eggs in one basket and stayed with Yale,” she says. “It was just too much to relocate or even do the testing at the other centers.”
To receive a liver transplant from a deceased donor, Zappone had to be sick enough that she qualified, but not so sick that she wouldn’t survive the surgery. It’s a thin line to walk; Dr. Liapakis says that 20% of patients die before receiving their transplant. “That is why we strongly encourage people to look for living donors,” she adds.
Living donation is an option for liver transplants because of the liver’s remarkable ability to regenerate. A person can donate a part of their liver, and it will return to almost its original size.
It can be done whenever a donor can be found, so patients who are able to choose this option may be able to have the transplant while they are still relatively healthy.
But finding an appropriate living donor is rarely easy. The donor and recipient need to have compatible blood type and body size, among other factors. None of Zappone’s family members were the right fit, and she didn’t feel comfortable asking friends to potentially undergo surgery for her.
“In this context, the Yale team has been working to develop patient education and support programming to assist patients in maximizing their opportunity for living donor liver transplant, and we are seeing a positive impact,” Dr. Liapakis says.
For Zappone, as the years went by, she was hospitalized multiple times and had to give up working. She hung on to the hope that she would at least stay alive long enough to see her son Nicholas get married in September 2016.
An organ arrives
By August 2016, Zappone’s health was quickly deteriorating. “She was very fragile. She needed to come in every week for protein infusions,” Dr. Liapakis says. And she had already lived beyond the average life expectancy for someone with her stage of NASH.
On Aug. 7, she was admitted to Yale New Haven Hospital in very serious condition. “I was so yellow, I scared the resident,” Zappone recalls. By the 24th, her doctors told her there was nothing else they could do for her, so she prepared to return home.
Her husband, Frank, who always had remained hopeful, felt the gravity. “I thought this was the end of the line,” he recalls. Zappone says she wasn’t sure quite what she felt at that moment. Her son’s wedding was approaching, and she still desperately wanted to attend.
But later that day, she received unexpected news: A liver was available. Surgery would take place as soon as it arrived from Maine. That’s when Zappone’s anxiety began to build. “’Holy God, this is really going to happen,’ I thought, and began to worry about all of the things that can go wrong in a nine-hour surgery,” she remembers.
A few hours later, Zappone and her husband heard the thunderous chopping of helicopter blades slicing through the air, and then landing on the roof. Her organ, nestled in a cooler, had arrived. The surgery, performed by James B. Yu, MD, and David Mulligan, MD, went smoothly, but there were complications soon after. Zappone had a severe reaction to one of her anti-rejection medications and ended up in the ICU.
The wedding date was drawing near. Though Zappone was able to transfer out of the ICU, she needed to remain hospitalized. She was incredibly weak. Her nurses scrambled to find a spot in the unit to decorate for a make-shift reception space. “The hospital staff was so excited about it. My son and his fiancée even decided to say their vows at the hospital, so I could be there,” says Zappone, now 69.
In the end, a hospital reception was not needed. Zappone was discharged the day before her son’s wedding. She happily sat in a wheelchair and watched him get married. Given the circumstances, the couple postponed the reception until the following spring.