Non-alcoholic steatohepatitis (NASH): Everything you need to know
What is NASH?
NASH (non-alcoholic steatohepatitis) occurs when an excess of fat accumulates in the liver (5 to 10% of the organ weight), and is not caused by alcohol consumption. It is a more serious form of NAFLD (Non-alcoholic fatty liver disease).
The liver is a very important organ in the human body, responsible for more than 600 functions! In particular, it acts as a filter for all the molecules that pass through the body (medicines, alcohol, food, etc.), but it is also responsible for processing fats: production, metabolization, transport and storage. When we eat, the liver transforms glucose (sugar) into fat so that it can be stored for a later time when the body needs it. When more than 5% of the cells in the liver are fat cells, it is considered simple fatty liver, or steatosis. In this case, the liver is enlarged and may appear white (or shiny) on ultrasound. This excess fat becomes toxic for the liver and causes inflammation; its cells become damaged and swell. NASH is thus defined by the presence of steatosis, inflammation, and therefore liver cell damage.
Inflammation and liver cell damage can further cause scar tissue formation, called “fibrosis”. If this scar tissue extends to the majority of the liver, NASH will progress to cirrhosis (a liver disease that leads to loss of organ function and numerous complications), liver failure or hepatocellular carcinoma (HCC), a type of liver cancer. At this point, liver transplant is considered according to patient eligibility (considering their overall health, age, phase of the disease, other coexisting conditions, if they are diabetic, etc.).
Patients with NAFLD usually do not experience symptoms, so it may often go undiagnosed and thus over time develop into NASH. However, some patients report experiencing:
- Moderate pain or discomfort in the upper right abdomen
- Loss of appetite
- Swelling of the legs
- Confusion and slurred speech
- Yellowing of the eyes or skin (jaundice)
- Accumulation of fluid in the abdomen (ascites)
Causes and risk factors
Western society's modern way of life contributes to the occurrence of NAFLD: unhealthy eating, sedentary professional lives and not enough physical activity. It is estimated that between 30 and 40% of US adults have NAFLD, and 3 to 12% have NASH.
But certain conditions also play a decisive role in the development of NASH. The following are thus considered risk factors:
- Excess weight
- Type 2 diabetes (T2D)
- Prediabetes, (a metabolic condition in which blood glucose levels that are higher than normal but not yet high enough to be classed as diabetes (fasting glucose levels of 5.5 mmol/L to 6.9 mmol/L, when normal fasting blood glucose is less than 5.5 mmol/L))
- Metabolic syndrome, a cluster of co-occurring physiological and biochemical conditions: excess weight, T2D, abnormal cholesterol levels (high LDL cholesterol, low HDL cholesterol), high triglyceride level, high blood pressure
Indeed, 8 out of 10 obese patients (79.1%) and 6 out of 10 diabetic patients (62.4%) are affected by NASH. In addition to obesity and diabetes, 80% of NASH patients suffer from dyslipidemia (too high a concentration of triglycerides and LDL cholesterol (bad cholesterol) in the blood).
Finally, other risk factors have been established: consumption of soft drinks (more than one can per day), smoking (more than 10 packs per year) and, of course, alcohol consumption, even in moderation.
Blood and imaging tests can detect liver abnormalities but cannot distinguish NASH from simple liver steatosis. Currently, the only way to make a diagnosis is by liver biopsy, which involves taking a sample of the liver for analysis. Given the risks and costs of this invasive examination, people with certain risk factors are generally given priority: 45 years and older, obese, type 2 diabetics or have an AST/ALAT ratio over 1 (the ratio of two enzymes in the liver).
In addition, biomarkers and fibroscan (a specialized ultrasound that measures fibrosis (scarring) and steatosis (fatty change) in the liver) are two innovative approaches still being evaluated to confirm the diagnosis of NASH.
Carenity members living with NASH waited on average more than five years for a diagnosis! According to our study, 70% of patients would have changed their diet and 60% would have taken up sport if they had learned of their disease earlier and had known more about it. The majority of patients (72%) were not familiar with the disease prior to their diagnosis, and 22% did not know what it entailed.
Read Anna's testimonial, a member of Carenity in Italy, who experienced a lengthy misdiagnosis.
“For me, NASH struck me like a bolt of lightning because previously all my doctors told me that I was just overweight and my situation could be completely reversed with some significant effort. NASH is a chronic inflammation of the liver, so it’s a disease that can actually have some serious consequences…”
No specific treatment for NASH exists at this time. Patient care consists primarily of a change in lifestyle (diet, physical activity). As for prescribed medications, they treat symptoms by targeting obesity, diabetes, high blood pressure, or dyslipidemia:
- Statins such as ATORVASTATIN to lower cholesterol and triglycerides
- Fibrates such as FENOFIBRATE to lower triglycerides
- METFORMIN to lower blood sugar levels
- Antihypertensive drugs such as LOSARTAN
- Anti-TNFα drugs to reduce inflammation
- ADIPONECTIN, which helps to regulate glucose levels and break down fatty acids.
There are also treatments with more specific targets:
- ARAMCHOL (Galmed) or VICTOZA which targets hepatic steatosis (NAFLD)
- TOBIRA, GALECTIN or CONATUS which target advanced fibrosis and cirrhosis
Dietary modification is strongly recommended in NASH patients. For those who are overweight or obese, the goal is to lose 7 to 10% of body weight. In general, dietary habits should be changed:
- Restriction of caloric intake
- Reduction in the consumption of saturated fatty acids (meat, butter, dairy products, etc.) in favor of mono- and polyunsaturated fatty acids (vegetable oils, fatty fish, oleaginous plants, etc.)
- Increase in fiber consumption, especially soluble fiber (fruit and vegetables, wholegrain cereals, etc.)
- Very limited or even no consumption of soft drinks, highly processed foods, high-glycemic index foods and alcohol (to be stopped in the case of severe fibrosis or cirrhosis)
It should be noted that coffee consumption seems to have a rather positive impact on hepatic steatosis and should not be limited (however it is recommended not to exceed six cups of coffee per day). Finally, non-personalized diets and slimming products are not recommended as they present a low benefit/risk ratio and are accompanied by weight regain when treatment is stopped.
It is important to be well monitored by a nutritionist, but psychological support is also recommended, especially if the patient has a history of disordered eating (sugar or salt addiction, bulimia, dependence on food to cope with stress, etc.).
Finally, regular and adapted physical activity is essential and complementary to a change in diet. Patients are encouraged to exercise two to four hours per week, divided into three to five sessions. The World Health Organization recommends at least 150 minutes of moderate or 75 minutes of intense activity each week. For example: walking or gardening for light activity; swimming, slow running or yoga for moderate activity; and tennis, cycling or fast running for intense activity. Resistance exercises are also effective. To combat sedentary lifestyles, these efforts must become a regular habit for the patient. For this reason, it is important to opt for an activity that the patient enjoys.
In the most advanced stages of the disease, particularly in cases of decompensated cirrhosis and/or cancer, the only remaining option may be a liver transplant. Unfortunately, not all patients are eligible for a liver transplant, waiting lists are long because organs are lacking and the procedure remains risky.
Transplants are allocated according to a comprehensive assessment of the patient’s liver and overall health as well as the patient’s Model for End-Stage Liver Disease (MELD) score. This score is calculated from the patient's INR, serum creatinine, serum bilirubin, and serum creatinine and helps doctors to determine the urgency of the transplant.
Following the transplant, a lifelong immunosuppressive treatment is necessary to keep the body from rejecting the new liver. This reduces the body's defenses against infection and can increase cardiovascular risks. It is also not always well accepted by the kidneys. A healthy lifestyle is therefore essential.
While bariatric surgery is considered to be the most radical and effective treatment for achieving significant and lasting weight loss in morbidly obese patients, its direct impact on NASH is not yet proven.
The search for new drugs is currently very active in the field of liver steatosis study. This is all the more so as the sedentary nature of the population is increasing the number of cases. Among the potential drugs, obeticholic acid (OCA) (a farnesoid X receptor agonist), elafibranor (a dual PPAR alpha and PPAR delta agonist), cenicriviroc (an inhibitor of CCR2 and CCR5 receptors) and selonsertib (an inhibitor of apoptosis signal-regulating kinase 1) are currently undergoing international therapeutic trials.
Research data has shown that OCA’s mode of action (Intercept) is not well understood within the scientific community. Some studies show efficacy on steatosis and fibrosis but not effect on inflammation. However, other studies show no significant effect on fibrosis or NASH. OCA, like elafibranor, could therefore fall into the category of medications targeting NASH, but its poor results on inflammation make it a special case to be closely monitored.
Alteration of the gut microbiota (the microorganisms that live in the intestine) using prebiotics, probiotics, symbiotics, antibiotics and even fecal transplantation are also being studied.
Research into the development of a biomarker diagnostic technique is ongoing. This technique would significantly change the expected detection rate of the disease because it is based on the use of a biomarker as an indicator of normal or disease-related biological processes that is objectively measured and evaluated. In the case of NASH, the measurement would be carried out by a simple blood test.
Non-alcoholic fatty liver disease : an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Preiss D, Sattar N. Clin Sci (Lond). 115(5):141-50
Association Française de Formation Médicale Continue en Hépato-Gastro-Entérologie
Published Aug 27, 2020