Rare Classroom: Nonalcoholic Steatohepatitis

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The rare disease that we will be learning about today is:

Nonalcoholic Steatohepatitis

What is Nonalcoholic Steatohepatitis?

  • It is the most severe form of non-alcoholic fatty liver disease (NAFLD), and is characterized by the presence of an abnormal accumulation of fat in the liver which in some individuals can progress to liver cell injury (hepatocellular ballooning) and inflammation. Hepatocellular ballooning and inflammation – sometimes called necroinflammation – are commonly considered as the drivers of disease progression, or as the underlying causes of the disease. 
  • This disease is not rare but is poorly understood, lacks effective treatments, and is becoming a growing public health problem​
  • As NASH evolves, over time it can result in excessive scarring in the liver (fibrosis), a natural response to injury which can lead to liver cirrhosis or liver cancer.
  • Nonalcoholic fatty liver disease is a leading cause of chronic liver disease that can lead to cirrhosis, hepatocellular cancer, and end-stage liver disease, and it is linked to elevated cardiovascular- and cancer-related morbidity and mortality.
  • Insulin resistance related to metabolic syndrome is the main pathogenic trigger that, in association with adverse genetic, lifestyle, and other factors, precipitates the development of non-alcoholic fatty liver disease.
  • NASH is usually a silent disease with few or no symptoms. ​As a result, it can progress for years – or even decades – undetected. ​As the liver damage becomes more severe, patients with NASH can progress to serious, life-threatening clinical outcomes, including decompensated cirrhosis (in which the liver is permanently damaged and scarred and unable to function properly), end-stage liver failure and its complications, hepatocellular carcinoma (HCC), the need for liver transplantation, and even death.
  • The true worldwide incidence rate of NAFLD/NASH is not known
    • It is difficult to obtain an accurate estimate of NASH prevalence given the fact that NASH is a silent disease, and a disease that remains difficult to diagnose for the time being, even though promising programs are currently in development. ​
    • In the United States, it is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people.​
    • But the trends are clear: non-alcoholic fatty liver disease (NAFLD) is growing to become the most common chronic liver condition in Western populations in relation to the obesity and type 2 diabetes epidemics, and the prevalence of NASH is also expected to increase by 63% between 2015 and 2030 (Estes 2018). 
    • The overall NASH prevalence in the adult population of developed countries has been estimated as high as 12% (Williams, 2011), with a heterogeneous repartition in relation to ethnicity:​
    • Hispanics: 19%​
    • Afro-Americans: 14%​
    • Caucasians: 10%​
    • Others: 7%​

How Do You Get It?

  • A precise cause for the disease isn’t known, but many people with NASH have other corresponding health conditions that appear to increase the risk.
  • Risk factors:
    • High cholesterol
    • Obesity
      • NAFLD is highly prevalent in populations suffering from obesity, but exact figures remain hard to estimate; in a study based on a population with severe obesity (BMI > 40), more than 90% of individuals had NAFLD.
      • As for NASH prevalence, a study aggregating data from more than 1.600 individuals who had bariatric surgery revealed a prevalence of 37%.
      • Obesity trends: Growing to epidemic proportions over the last 30 years, obesity is expected to continue to keep increasing over the next decades, albeit at a reduced pace. According to OECD, 47% of the adult population in the United States will suffer from obesity by 2030, compared to 37.7% in 2014. 
    • High triglycerides
    • Insulin resistance
    • High cholesterol
    • Type 2 diabetes
      • NAFLD prevalence in populations with type 2 diabetes is estimated at approximately 70% in several studies; this estimation is also used in the AASLD Practice Guidelines. Depending on the methodologies and populations used in the respective studies, estimations of NASH prevalence in this population range from 22% to 70% (Williams et al. 2011 and Bazick et al. 2015).​
      • Type 2 diabetes trends: worldwide diabetes rates are expected to grow by about 55% by the year 2035 according to the International Diabetes Federation, which means that this population at risk of NAFLD/NASH will increase dramatically over the next decades.​
    • Certain genetic variants
      • Studies indicate that the activity (expression) of the PNPLA3 gene decreases during periods without food (fasting) and increases after eating, suggesting that the amount of adiponutrin protein produced is regulated as needed to help process and store fats in the diet. ​
      • The PNPLA3 gene variation associated with NAFLD is thought to lead to increased production and decreased breakdown of fats in the liver. ​
    • Family history
      • Inheritance Pattern- An increased risk of developing NAFLD can be passed through generations in families, but the inheritance pattern is unknown. Variations in several genes as well as lifestyle and environmental factors contribute to the risk of developing this complex disorder.
    • Drugs and toxins – Several drugs used to treat other medical conditions have been linked to NASH, including amiodarone (brand names: CorderonePacerone), tamoxifen (brand names: NolvadexTamone), perhexiline maleate (brand name: Pexhid), steroids (egprednisone, hydrocortisone), and synthetic estrogens. 
    • Certain pesticides have also been linked to NASH.
  • Pediatric NAFLD and NASH
    • Non-alcoholic fatty liver disease in children is a major health concern for the medical community. ​
    • The phenomenon was first reported in 1983 and has since become a leading cause of childhood chronic liver disease which has also been fueled by the growing childhood obesity epidemic.
    • ​Several studies have found that approximately 10% of the pediatric population had NAFLD, with a higher incidence in children of Hispanic origin (Schwimmer JB et al, 2006). ​
    • For example, a study conducted in the United States in more than 8.500 individuals estimated that 10% and 3% of US adolescents were affected respectively by NAFLD and NASH (Selvakumar, Pediatric Clinics of North America 2017).​

What Are The Symptoms?

  • NASH is usually a silent disease with few or no symptoms.
  • As a result, it can progress for years – or even decades – undetected.
  • There are often no outward signs or symptoms associated with NASH. The most common symptoms are:
    • Fatigue​​
    • Pain in the upper right abdomen (usually mild)​​
    • NASH may lead to cirrhosis of the liver, causing one or more of the following symptoms as the condition progresses:​​
    • Bleeding easily​​
    • Bruising easily​
  • As a progressive disease, the longer you have NASH, the harder it becomes for your liver to do its job. The stages of NASH include:​
    • SteatosisSteatosis means you have abnormal levels of fat in your liver. With proper treatment, liver damage in this stage is reversible.​
    • Steatohepatitis: As your condition becomes more severe, healthy liver tissue is replaced with fat and becomes inflamed. It takes advanced care from a liver disease expert to reverse this stage of illness.​
    • Cirrhosis: Cirrhosis happens when the damage becomes so severe that scar tissue begins to take over your liver. Beyond a certain point, there are not many treatments that can save you from liver failure.

How Is It Treated?

  • NASH can progress to more serious disease stages, such as advanced fibrosis, cirrhosis, liver failure, or liver cancer.​
  • A liver transplant might then be required, but this is a risky surgical procedure associated with several types of complications, not to mention long waiting lists due to the lack of available healthy organs from donors, or eligibility issues related to patient condition.​
  • Lifestyle modification, consisting of diet and exercise, is the cornerstone of therapy for NASH and has been shown by many studies to improve liver histology. Weight loss is the cornerstone treatment of non-alcoholic fatty liver disease; however, it is difficult to achieve and maintain, so pharmacotherapy was developed. Diabetic and cholesterol-lowering medications may be employed.
  • The type of doctors most qualified to treat nonalcoholic fatty liver disease (NAFLD) is gastroenterologists or liver specialists, also known as hepatologists. Many people who have NAFLD seek and benefit from the help of different kinds of healthcare professionals, including their primary care physician, a nutritionist or dietitian and in many cases, a cardiologist.
  • Approved medications (Outside of the US)
    • Ursodiol (brand name Sorbidiol)
    • Metadoxine (brand name Abrixone)
  • Vitamin E: For people with severe forms of NASH who do not also have diabetes or heart disease, healthcare providers sometimes recommend supplements of vitamin E. There is some evidence that vitamin E might reduce some of the liver damage that occurs as part of NASH, but the evidence is weak, and there is also evidence that high-doses of vitamin E supplements increase the risk of death. Do not take vitamin E unless your healthcare provider recommends it.
  • People with NASH should avoid alcohol consumption entirely as this can worsen the condition of the liver.

Where Can I Learn More???

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