Struggling to find a foothold with NAFLD

Karen Titus

March 2020—For pathologists, a first look at nonalcoholic fatty liver disease can be jarring.

Purva Gopal, MD, associate professor of pathology, UT Southwestern Medical Center, has seen her share of initial biopsies on patients whose “livers are already cirrhotic,” she says.

So has Cynthia Guy, MD, professor, Department of Pathology, and chief of the liver and GI surgical pathology section, Duke University Health System. It’s not a good look, obviously, so it’s one she’s doing her best to share with clinical colleagues.

At her institution, pathologists have built a strong connection with the hepatologists and gastroenterologists, she says, and NAFLD is part of the regular show-and-tell. “That raises awareness,” says Dr. Guy, who is also director of the GI/liver surgical pathology fellowship program. “Because we do have those discussions about the 30-year-old, overweight but otherwise apparently healthy patient who turns out to have cirrhosis from NAFLD. And just talking about that case points out that this didn’t just happen last year. They probably had this problem all during their 20s—and now it’s in the very, very severe end stage.”

How does such advanced disease make it past the warning signs of laboratory tests and the eyes of concerned clinicians?

How much time do you have?

“It’s multifactorial; it’s very complex,” Dr. Guy warns.

Arjmand Mufti, MD, transplant hepatologist, UT Southwestern Medical Center, agrees. “It’s a complicated disease, with lots of things contributing to it. There are lots of moving parts that need to be in play,” he says, then adds: “There are no sound bites for this story.”

The answer is simple yet complicated, like a Shakespeare plot. As Brutus learned, it was easy to kill Caesar, but bringing order to the postmortem Republic was not. And while those portents of doom seemed obvious in retrospect (shrieking ghosts, ghastly women, disinterested lions), they were also easy to misinterpret, making it feasible for Caesar to go forth on March 15.

Likewise, tackling NAFLD has the appearance of being straightforward. Use basic tests (ALT, AST) and follow up abnormal results. Calculate surrogate markers for fibrosis with tests that have already gained a strong foothold outside the United States, such as the NAFLD fibrosis score, Fibrosis-4 test,

Enhanced Liver Fibrosis, or FibroTest. Refer patients to hepatologists. Perform a liver biopsy, which is the gold standard for diagnosing nonalcoholic steatohepatitis. (NAFLD encompasses simple steatosis and NASH.) Intervene early with appropriate treatments.

And yet, as the experiences of Drs. Gopal and Guy show, failures can occur at each step.

The goals are clear, says Amit Singal, MD, associate professor of medicine, clinical chief of hepatology, and medical director of the liver tumor program at UT Southwestern, but the steps to improving response to NAFLD can seem daunting.

“The ideal thing would be to decrease obesity and diabetes in the population and make NAFLD less prevalent,” Dr. Singal says. Prevention is key, in other words, with healthier lifestyles or some degree of medication that prevents liver fibrosis from developing even in the presence of metabolic syndrome. But that’s not happening. Score that medicine 0, NAFLD 1.

The next step would be a medication to treat both metabolic syndrome as well as liver inflammation and fibrosis, he says. Such a drug doesn’t exist. Score: 0–2.

The third step, Dr. Singal says, is a serum biomarker to accurately predict development of fatty liver disease in patients with metabolic syndrome and obesity. 0–3.

Finally, he’d like to see better biomarkers for noninvasive assessment of fibrosis. “There are several that are good. None are perfect,” says Dr. Singal. 0–4.

Make things too simple, and any useful meaning is lost. Richard III is just a cranky uncle in the market for a new horse. King Lear needs better estate planning. The Macbeths should not be hosting dinner parties.

The more complicated story demands exploration, say NAFLD experts. The disease already affects far too many patients, and the problem is likely to get worse. NAFLD has already replaced hepatitis C as the No. 1 reason for liver transplants. As the hepatic manifestation of metabolic syndrome, NAFLD is tightly bound to the continual rise in obesity and type two diabetes. “Some people consider this to be an epidemic almost worldwide,” Dr. Gopal says.

The consequences for patients are severe. Some 70 to 75 percent of patients with NAFLD will have isolated fatty liver, says Dr. Mufti, with no to minimal progression to fibrosis. But the rest will have NASH. “These are the patients we need to identify, because they have increased cardiovascular death, they have increased malignancy, they have increased liver death. And if you have fibrosis, that is the thing that portends a worse diagnosis.

“This is where I think we could do a better job,” continues Dr. Mufti, who is also fellowship program director for digestive and liver diseases.

Who, exactly, needs to do a better job is also a bit complicated. The predicted explosion of the disease could alter the practices of pathologists and clinicians. Pathologists who aren’t liver specialists may find themselves being asked to perform more liver biopsies. And if there aren’t enough hepatologists to handle referrals, more primary care physicians could find themselves on the frontlines of trying to care for patients with the disease.

“This is not an issue that’s going to go away,” Dr. Mufti says. “It’s only going to grow.”

The first step is to continue to build awareness of NAFLD, says Dr. Guy. In her view, primary care physicians, focused on hypertension, hyperlipidemia, prediabetes, obesity, and other symptoms of metabolic syndrome, may not be aware of an underlying liver problem.

Laboratories can help point the way. But there is, naturally, no single diagnostic test for NAFLD. “Right now, it remains largely a diagnosis of exclusion,” Dr. Singal says. “Providers have patients who have chronic liver disease with elevated liver enzymes or other signs of chronic liver disease, and they must exclude the presence of viral hepatitis, other metabolic liver diseases, alcohol abuse. And then in the right clinical setting, such as somebody with obesity or metabolic syndrome, they can make a diagnosis of NAFLD.

“There are the patients who may have ‘lean’ NASH—they won’t have the phenotype that makes you think of NASH,” he continues. “But they have chronic liver disease and the testing for other liver diseases is negative. In those cases you may consider a biopsy to make a diagnosis.”

Often the initial tests for NAFLD—its iambic pentameter, if you will—are ALT and AST. While not specific for NAFLD, their presence in routine panels can offer early clues to possible problems. Both are poor markers of liver function, however, and physicians may not make the connection to possible NAFLD.

“If the ALT is elevated, then that’s informative, whether or not the patient has metabolic conditions,” says Elizabeth M. Brunt, MD, emeritus professor of pathology, Department of Pathology and Immunology, Washington University in St. Louis. “But if it’s not elevated, it’s not informative. It’s hard for people to understand that this disease can be quiet. If the patient is not obese, that doesn’t necessarily clear them of the possibility of having the disease. And if they have other metabolic problems, they can still have this disease.”

Even when liver enzymes are indicative of a problem, it’s not uncommon for physicians to look at AST and ALT in isolation, says Dr. Mufti. Nor is it uncommon for these results to be only very mildly elevated, prompting clinicians to say, in essence: Nothing to see here—we’ll just follow them when you come back for your next visit.

“That’s what a lot of people do now,” Dr. Mufti says. But if that low-key response happens year after year, “That’s where we get into trouble. We have patients who’ve had mildly abnormal liver function tests for 15 years, and they’ve had ongoing inflammation, and then they come in with cirrhosis.”

It can be an understandable response, however. Sometimes that blinking of the “check engine” light is merely annoying.

Says Dr. Brunt: “Often it takes an astute clinician to realize that perhaps the liver tests are elevated. And unfortunately, the liver tests aren’t always elevated.” And if they are, it doesn’t necessarily point to NAFLD. Certain medications, for example, can raise liver enzymes, as can viral hepatitis and other chronic liver diseases.

It’s also possible for someone to have cirrhosis without the red flag of elevated enzymes—they can normalize in a patient with advanced fibrosis, says Dr. Gopal. “But hopefully they’d have some other clinical manifestation of cirrhosis that the clinician would pick up on.”

Even if liver function tests are normal, patients with risk factors for metabolic syndrome can benefit from simple lab tests. The questions are straightforward, Dr. Mufti says: What’s happened to the platelet count? Was the platelet count ordered? Have the albumin levels fallen? Has the bilirubin been rising? Is there anything that is telling you that the patient may have evidence of portal hypertension based on labs? “You don’t even have to have imaging,” Dr. Mufti says. “A lot of this is based on labs.”

But without an awareness of the disease itself, clinicians may not put the pieces together to see the full picture. And laboratories aren’t necessarily putting them together for the clinician, either, Dr. Brunt says. “But we’re often not asked to.”

Even if someone were assembling the pieces, it can be hard to see the full picture, Dr. Guy says. Because NAFLD is a systemic inflammatory disorder, patients often have elevated autoantibodies, such as antinuclear antibody or anti-smooth muscle antibody. Someone less familiar with that nuance might be tempted to assume autoimmune hepatitis. “Which it could be,” Dr. Guy acknowledges. “But almost a third of fatty liver disease patients will have low-titer positivity for ANA and SMA.”

Patients with fatty liver disease can have elevated alkaline phosphatase and gamma-glutamyl transferase, Dr. Guy continues, which typically points to a biliary problem. “And we don’t understand exactly why, but 20 to 25 percent of [people] with NAFLD can have an elevated alkaline phosphatase and GGT.”

Dr. Guy continues: “Even with a patient sitting in front of a very experienced hepatologist [who] has the full panel of labs, they may not know exactly what disease the patient has.” In her observation, “That’s why a lot of the really good hepatologists get a liver biopsy toward the beginning of the workup, because they know they can be fooled by the labs alone.”

That assumes, of course, that a patient is indeed sitting in front of a physician. Dr. Gopal says when she sees a cirrhotic liver, “It’s not necessarily because the physician isn’t picking up on it sooner.” Patients don’t always have routine checkups and may see a physician only once they’re feeling ill.

Even a discussion of normal/abnormal can create confusion.

As Dr. Mufti ponders this, he talks about the upper limits of normal for ALT. He looks to the guidelines from the American Association for the Study of Liver Diseases, which uses 29 to 33 for men, and 19 to 25 for women; in practice, “We’re really looking at 35 for men and 25 for women, just to keep it simple.”

Nevertheless, he continues, it’s not uncommon for lab results to report an upper limit of normal of 50 or 60. “So if we get a lab value of 50, it’s considered normal,” even though upper limits of normal of 25 and 35 are most useful to him. Moreover, a patient with a 45 one year, followed by 70 the following year, doesn’t necessarily mean “it’s a thing,” as he puts it. “We need to keep in mind that these are all abnormal, and to think about what being abnormal means.”

The broader goal, he says, is to get care providers to think about the possibility of a NAFLD diagnosis sooner, and then to use basic tests to differentiate those who will progress.

“We use a spectrum of things to assess someone’s risk,” Dr. Mufti says. “The important thing to remember from our perspective is that normal liver function tests on their own do not mitigate someone from having significant risks.”

A patient with other risk factors—metabolic syndrome, diabetes, hypertension, hyperlipidemia—are at higher risk for NAFLD. Dr. Mufti cites data that suggest that among patients with type two diabetes and who have normal liver enzymes, about half may have NAFLD, while half of those patients will have nonalcoholic steatohepatitis. “So we may look to triglycerides and lipid levels,” Dr. Mufti says, noting that serum triglycerides are significantly higher in patients with NASH.

Surrogate markers for fibrosis are the next level of testing. Dr. Mufti says his regular practice is to “get a baseline, noninvasive marker in every single patient I see in clinical practice,” as a way to screen for fibrosis.