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Central Research
Liver cirrhosis and minimal hepatic encephalopathy, their impact on quality of life and the role of molecular biology
Throughout history, liver diseases have been a major health problem and their consequences are significantly reflected in human behavior.
In ancient Mesopotamia (2000 BC) powers of augury and divinity were attributed to the liver, then it was called “soul” or “humor”. In traditional Chinese medicine (Neiching, 1000 BC), the liver was considered a storehouse of blood containing the soul. Hippocrates described a patient with hepatitis as one who “barked like a dog and could not say things that could be understood.” For his part, William Shakespeare exposes the behavior of an alcoholic gentleman with chronic dementia and protein intolerance.
Sir Andrew Aguecheek, star of the comedy Twelfth Night, is considered one of the most modern descriptions of hepatic encephalopathy of the last 400 years. It is described by Dr. William Summerskill in the journals The Lancet and Gut as Aguecheek’s disease. Thus, the relationship between the liver and brain function has been described throughout history.
Liver disease can occur for different reasons: viral infections (hepatitis B and hepatitis C), alcohol intake or fat accumulation in non-alcoholic fatty liver disease. Recently, the spectrum of liver damage in COVID-19 has been described, ranging from direct SARS-CoV-2 infection, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes (adverse drug reactions), and ventilation, to exacerbation of underlying liver disease.(1)
Every year 2 million people around the world die from liver disease. In addition, it represents a high burden of disability and increased use of health resources; 3.5% of deaths worldwide are due to liver diseases(2).
In Mexico, liver cirrhosis is the third most common cause of mortality in men and the seventh in women. As chronic liver disease progresses, patients develop complications of hepatocellular dysfunction and portal hypertension that contribute to liver-related morbidity and mortality. Hepatic encephalopathy is a common complication in chronic liver disease.
Hepatic encephalopathy (HE)
It is a spectrum of potentially reversible neurological and psychiatric disorders whose clinical manifestations can range from subclinical alteration of mental status to coma. Encephalopathy has been classified based on clinical response, with the West Haven criteria, identifying four levels. The latest consensus of the ISHEN (International Society for Hepatic Encephalopathy and Nitrogen
Metabolism) classifies HE into two large groups: the minimum HE and the overt HE. In practical terms, HE can be classified as covert HE, which is one comprising minimum HE and West Haven grade I (see Table 1). Overt EH is characterized by being clinically evident without the need for psychometric or neuropsychological testing and comprises grades II to IV of the West Haven classification. In recent years, level one was subdivided based on a model that exposes the need for early detection of the stage of the disease(3).
Minimal hepatic encephalopathy (MHE)
Also called subclinical hepatic encephalopathy, it represents the earliest and mildest form of hepatic encephalopathy (HE). It refers to a condition defined by the existence of a series of neurophysiological and psychiatric alterations. Minimal hepatic encephalopathy can affect up to 80% of patients with liver cirrhosis. It is characterized by the deterioration of cognitive function, mainly in the domains of attention, memory, speed of response, vigilance, and integrative function. Patients with MHE have reduced performance in daily activities, so they have a shorter productive life.
In 1950, monomorphic slow waves were observed for the first time in the frontal regions of the electroencephalograms of patients with MHE(3). Although there is currently no gold standard for its diagnosis, today we have useful and easy-to-apply diagnostic tools, such as Stroop EncephalApp, which is a digitized version of the original Stroop test used to assess resistance to mental stress.
It was recently introduced as a tool for the diagnosis of MHE, however, it is necessary to validate these tests in our population(4).
Neuropsychiatric aspects in minimal hepatic encephalopathy
The effects on cognition define EH as a neuropsychological syndrome with an impact on cognitive, affective, and motor functions observed to a greater extent in executive processes, especially attention. This is associated with a multitude of negative effects on the individual’s health-related quality of life, from sleep disturbances, gait disturbances with increased risk of falls, and the ability to drive vehicles.
On the other hand, a prevalence of up to 45% of depression and anxious symptoms associated with this condition is also described. Recently, and through the approach of brain function as an organization in networks, it is observed that in the MHE brain functioning is altered in regions linked to cognitive processes whose alteration is observed in the clinic.
Expectations of early diagnosis by metabolic markers
Normal brain function depends in several ways on the normal functioning of the liver. Although the brain is protected from neurotoxic substances by the blood-brain barrier (characteristic of blood vessels in the brain that prevents the passage of many compounds from the blood into brain tissue), some neurotoxins can penetrate this barrier after injury to the liver such as cirrhosis. This liver disease induces an increase in neurotoxic substances such as ammonium and manganese, which in turn induce oxidative stress by crossing the blood-brain barrier, causing damage to neurotransmission, failure in energy synthesis and finally cell death (represented schematically in Figure 2).
Molecular diagnostics
Hepatic encephalopathy is linked to molecular alterations resulting from liver damage. One of the most common is the decrease in the formation of urea, with the consequent elevation of ammonium levels in the blood. Ammonium turns out to be very toxic to the brain and among other things causes an increase in water in the tissue (edema) (see Fig. 1).
Detecting damage at an early stage is undoubtedly a great challenge. The liver works by containing or transforming molecules into an organ that detoxifies, turning the most harmful into less harmful ones. Thus, when the intestine produces ammonium, the liver transforms it into urea, or when we eat fats or excess amino acids, our liver transforms them into energy; however, as our liver receives more and more work and more toxic, it is damaged and obviously no longer does its job so efficiently. This increases blood molecules that reach the brain.
Conclusions
Investment and innovation are vital to maintain adequate surveillance of chronic liver disease and its complications, mainly those related to neurodegeneration. Funding for liver disease, liver cancer, viral hepatitis, organ transplantation, obesity, and alcohol consumption is projected to decline in health systems, which may hamper these efforts. Continued attempts to track the burden of liver disease will help identify priorities for clinical care. Liver cirrhosis and its complications represent an important burden in the country, the timely diagnosis of each of these complications and specifically of minimal hepatic encephalopathy is fundamental since it directly impacts the quality of life of patients. Improving screening tests should be a priority in the coming years.
Dr. Ana Villaseñor-Todd
Scientist, doctor by profession and Mexican businesswoman noted for her studies in minimal hepatic encephalopathy, oxidative stress, quality of life and social cognition. Certified by the Pan American Health Organization (PAHO) as a facilitator of MhGap; CEO VICOMMA Group.
Technical Committee:
Rosa del Carmen Lopez-Sanchez, Bernardo Ng, Jose Asención HernandezHernandez, Xochitl Duque-Alarcon, Carlos Alejandro Cortes-Hernandez
References
Nardo, A. D., Schneeweiss-Gleixner, M., Bakail, M., Dixon, E. D., Lax, S. F., & Trauner, M. (2021). Pathophysiological mechanisms of liver injury in COVID-19. Liver international: Official Journal of the International Association for the Study of the Liver ,41(1), 20–32. https://doi.org/10.1111/liv.14730
Moon, A. M., Singal, A. G., & Tapper, E. B. (2020). Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis. Clinical gastroenterology and hepatology: The official clinical practice journal of the American Gastroenterological Association, 18(12), 2650–2666. https://doi.org/10.1016/j.cgh.2019.07.060
Karanfilian, B. V., Park, T., Senatore, F., & Rustgi, V. K. (2020). Minimal Hepatic Encephalopathy. Clinics in liver disease,24 (2), 209–218. https://doi.org/10.1016/j.cld.2020.01.012
