Cirrhosis, Now Linked to NAFLD, Presents Management Challenges

Cirrhosis, or advanced fibrosis of the liver, presents with many challenges such as complications associated with portal hypertension, but in today’s medical climate, it must also be considered in relation to nonalcoholic fatty liver disease, an emerging epidemic.

The two most common causes of cirrhosis in the United States are hepatitis C and alcoholic liver disease, according to Sujit V. Janardhan, MD, PhD, an assistant professor of medicine at Rush University Medical Center in Chicago. “However, the most rapidly growing cause of cirrhosis is actually nonalcoholic fatty liver disease,” he told Healio Gastroenterology.

A study in Gastroenterology showed that in 2013 NAFLD became the second leading liver disease among adults waiting for a liver transplant. “From 2004 to 2013, NAFLD as an etiology of liver disease for new transplant waitlist recipients increased by 170%,” Janardhan said.

Sujit V. Janardhan

Janardhan is not surprised by the study’s findings. “I personally probably see more patients with NAFLD than with hepatitis C,” he said. He attributes the increased incidence of NAFLD to the obesity epidemic and obesity-related disorders, “specifically the metabolic syndrome, which consists of prediabetes or diabetes, elevated waist circumference, high blood pressure and abnormal cholesterol or triglycerides. NAFLD is the liver manifestation of this metabolic syndrome.”

As the name implies, fatty liver is a liver with excessive fat. “Fatty liver in some people can progress to cirrhosis of the liver,” Naga P. Chalasani, MD, a professor of medicine at Indiana University School of Medicine in Indianapolis, told Healio Gastroenterology. “Fatty liver is largely related to obesity and diabetes, and may end up becoming the most common cause of cirrhosis in the Western world.”

Conversely, according to Chalasani, the incidence of cirrhosis and liver failure due to hepatitis C is decreasing, due to powerful antiviral medications, while the incidence of cirrhosis due to fatty liver and alcoholic liver disease is increasing.

Diagnosing Cirrhosis

Chalasani said cirrhosis itself is not difficult to diagnosis in most people, as diagnosis is based on blood work, a physical work-up and cross-sectional imaging such as liver ultrasound or CT scan. Occasionally, though, a liver biopsy may be warranted.

FibroScan (Echosens) is a new technique that helps manage patients with chronic liver disease and cirrhosis. “This is point-of-care testing that can be done in the clinic by non-physician technicians,” Chalasani said. The scan provides both a liver stiffness score (a marker of liver fibrosis) and a controlled attenuation parameter (AP) score (an estimate of liver fat quantity). “The higher the scores (eg, greater than 14-15 kPa), the more likely an individual has cirrhosis,” he said.

Naga P. Chalasani

An MRI-based test called elastography is also sometimes used to diagnose cirrhosis. “This imaging technique gives not only the fibrosis score, but looks at the liver as well,” Chalasani said. For example, if a patient has a tumor in the liver, MRI will detect it, whereas FibroScan “is not really visualizing the liver. It is limited to providing an estimate of liver fibrosis stage and the quantity of liver fat.”

Complications of Cirrhosis

“When the liver becomes very scarred, it also becomes very stiff,” Janardhan explained. “Therefore, it becomes very difficult for blood to flow through the liver. This causes high pressure in the blood vessels between the intestine and the liver,” a phenomenon known as portal hypertension.

Many of the complications of cirrhosis are related to portal hypertension. For example, variceal bleeding is caused by blood trying to get around the liver through the esophagus in dilated blood vessels known as varices. “With high pressure, those blood vessels in the esophagus can become extremely swollen and can burst, causing life-threatening bleeding,” Janardhan said.

Likewise, high pressure in blood vessels between the intestine and the liver can cause fluid to leak from those blood vessels, which causes an accumulation of fluid in the belly known as ascites.

Similarly, when blood attempts to flow around the liver rather than through the liver, the liver is unable to detoxify the blood, which can lead to cognitive confusion known as hepatic encephalopathy.

The screening process for cirrhosis includes screening for these three complications. “Hepatic encephalopathy is mostly a clinical diagnosis, although there are certain applications and tests that can be performed to detect even very subtle encephalopathy (covert encephalopathy),” Janardhan said. Ascites, on the other hand, is often assessed by physical exam, as well as imaging of the abdomen by ultrasound. Varices is generally screened by upper endoscopy.

Patients with compensated cirrhosis — those without any clinical signs of cirrhosis-related complications — can often visit a specialist once every 6 months, according to Janardhan. “Patients with cirrhosis also have a very high risk of developing liver cancer, so they need to be screened every 6 months for liver cancer, which is usually done through ultrasound,” he said. “However, some practitioners screen outside of the guidelines by also incorporating cross-sectional imaging, such as CT scan and MRI, intermittently, because of the increased sensitivity in detecting cancer in those tests.”

Treating Complications

Chalasani agreed that compensated cirrhosis is more easily managed. “By seeing patients generally once every 6 months, they tend to do well,” he told Healio Gastroenterology. But when patients transition to decompensated cirrhosis, “this is when they start having complications. As the cirrhosis worsens, it can be quite challenging. Sometimes you may need to see such patients frequently. Unfortunately, they may also be in and out of the hospital, due to complications.”

Treating decompensated cirrhosis is complex, according to Fred F. Poordad, MD,vice president of academic and clinical affairs at the Texas Liver Institute in San Antonio. “Treatment really means treating complications related to portal hypertension,” he said in an interview with Healio Gastroenterology. “Esophageal and gastric varices are treated by ligating veins that are bleeding, or prone to bleeding, most commonly done by banding, to effectively thrombose the vessel and decrease the risk of rupture and bleeding.”

Poordad said that ascites entails restricting sodium and using diuretic combinations to allow urinary excretion of free water. “This is sometimes inadequate or limited by azotemia, which then leads to secondary methods of controlling ascites or hydrothorax, namely placement of vascular shunts, such as a transjugular intrahepatic portosystemic shunt (TIPS), which allows communication between the portal vein and hepatic vein, allowing for decompression of portal pressures,” he said.

As a result, both varices and ascites can be relieved. However, the presence of large ascites or past infection “usually requires a preventative measure of antibiotics to ensure no future infection, or spontaneous bacterial peritonitis (SBP), which can carry a high mortality rate,” Poordad said.

Fred F. Poordad

On the other hand, treatment for hepatic encephalopathy requires reduction of ammonia exposure and other gut-derived toxins by employing agents that “increase excretion (lactulose) or change intestinal milieu (rifaximin [Xifaxan, Salix Pharmaceuticals]) to achieve improved neurocognitive function,” Poordad said.

Additionally, patients with cirrhosis are growing older and are confronted with comorbid conditions, according to Jasmohan S. Bajaj, MD, an associate professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at Virginia Commonwealth University and McGuire Veterans Administration Medical Center in Richmond, Va. “There is also a decreasing impact of variceal bleeding, while hepatic encephalopathy, end-stage organ failures and infections are gaining importance,” he told Healio Gastroenterology.

Bajaj said there have been recent trials to study the eradication of hepatitis C on the prognosis of cirrhosis; using regorafenib (Stivarga, Bayer) to treat advanced hepatocellular carcinoma (HCC); and to diagnose the earliest stages of hepatic encephalopathy with methods such as the smartphone application EncephalApp–Stroop Test to evaluate a user’s mental speed.

Bajaj was the lead researcher in a study of a large cohort of patients with cirrhosis who were followed for 3 months. Results, which appeared in Hepatology in 2016, showed a 53% readmission rate, “of which the highest rate was for hepatic encephalopathy,” Bajaj told Healio Gastroenterology.

Of the 1,353 patients enrolled in the study, 1,013 had 3-month outcomes. “Patients with worse Model for End-Stage Liver Disease score or diabetes, those taking prophylactic antibiotics and those with prior hepatic encephalopathy were most likely to be readmitted,” Bajaj said.

Further, 30% of readmissions could not be predicted.

Besides the common complications that can arise from cirrhosis, major challenges are emerging for hepatic encephalopathy, “which is neurocognitive impairment due to buildup of toxins from the failing liver, and infections that can result in end-stage organ failures, such as acute-on-chronic liver failure (ACLF) and a heavy burden of readmissions,” Bajaj said.

Jasmohan S. Bajaj

Bajaj said the role of HCV eradication needs to be defined in long-term studies of patients with cirrhosis. There is also the need to generate multi-center strategies “to prevent and treat these changing populations of cirrhotic patients,”he said.

To prevent further damage to the cirrhotic liver, “it is important to ensure patients have been vaccinated or already have immunity to hepatitis A and B,” Poordad added. Avoiding raw shellfish and assessing medications for potential liver toxicity are also recommended. “Some medications, though, require dose adjustments for cirrhosis and some are potentially more toxic in advanced liver disease,” he said.

Chalasani said as a rule of thumb, a general gastroenterologist should refer a patient to a transplant hepatologist when the patient develops complications of cirrhosis, such as bleeding, encephalopathy, ascites or liver tumors. “The transplant hepatologist can explore whether a liver transplantation is the correct course of action,” he said. “Of 100 patients with cirrhosis, at any given time about 20% to 25% will have decompensated cirrhosis and thus may be suitable for liver transplantation.”

Likewise, if a patient with cirrhosis develops a liver cancer, Poordad said, “Urgent referral is required. Most hepatologists are happy to have cirrhotics referred at any stage of a patient’s disease, to ensure they receive the highest chance of long-term survival.”

However, only about 20% of referrals undergo liver transplant.

Emerging Treatments

Chalasani is encouraged by the testing of some novel medical treatments to improve fibrosis, especially in people with fatty liver disease. “I think this would be potentially an injection, either parenteral or a small molecule taken by mouth,” he said. “The goal is to improve scar tissue within the liver.”

Janardhan said that by removing the source of the inflammation that leads to scar tissue formation in the liver, some of the scar tissue might get better. “However, there is a point of no return,” he said. “When a patient develops decompensated cirrhosis, it is very difficult for that liver to improve to the point where the liver can completely repair itself.”

Janardhan said the 10-year survival for a patient with compensated cirrhosis, and who remains in a compensated state, can be up to 75%. “This pales in comparison to a person with decompensated cirrhosis, for which the survival rate is less than 25%,” he said.

Poordad said the most exciting treatments for cirrhosis are not yet available, but should be in a few years; namely, antifibrotics, “which promise to reverse the scarring process that leads to cirrhosis in the first place. These agents, many of which are very early in development, aim to either arrest or even regress fibrosis and hence, lead to improved hepatic function and low portal venous pressures.”

Poordad expects these agents to take center stage in 5 to 10 years, and fundamentally change the way physicians treat cirrhosis.

Meanwhile, patients with cirrhosis “require a highly organized health care system and frequent visits with health care providers,” Poordad said. “Hepatology programs with experience in dealing with these complex patients are generally required to optimize management. The future of treating cirrhosis will also involve the appropriate management of the metabolic syndrome, as this is the next wave of cirrhosis beyond the aging hepatitis C population. New therapies aimed at treating fatty liver with antifibrotic features will likely be the best medications for this rising epidemic of liver disease.” – by Bob Kronemyer

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For more information:
Jasmohan S. Bajaj, MD, can be reached at
Naga P. Chalasani, MD, can be reached at
Sujit V. Janardhan, MD, PhD, can be reached at
Fred F. Poordad, MD, can be reached at

Disclosures: Bajaj is a consultant to Valeant, Grifols, Abbott and Norgine. Chalasani has consulting agreements and research grant support from several pharmaceutical companies, but none represent potential conflicts of interest for this article. Janardhan reports no relevant financial disclosures. Poordad reports he received grant/research support from AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals and ZymoGenetics. He is also a speaker for Gilead, Kadmon, Merck, Onyx/Bayer, Genentech, GlaxoSmithKline, Salix and Vertex, as well as a consultant/advisor for AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance and Vertex.


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Sean Hendrickson