Hepato-neuro lab

History of HE

Early symptoms associated with hepatic encephalopathy go back to 1860 in “A clinical treatise on diseases of the liver” by Dr Frerichs. He describes several cases of his patients :

Cases have repeatedly occurred to me, in which individuals who for a long period have suffered from cirrhosis of the liver, have suddenly presented a series of morbid symptoms which are foreign to that disease. They have become unconscious, and have been afterwards seized with noisy delirium, from which they passed to deep coma,and in this state have died.

It opens the door to research by specifying that the causes were unknown to him.

It still remains for us to allude to the causes of the nervous symptoms, the delirium, the somnolence, and the coma, which are frequently observed in fevers complicated with jaundice.

As soon as 1877, a Russian, Nikolai Vladimirovich Eck developed a model to study the liver similar to the portosytemic derivation, the fistula of Eck in 8 dogs. A colleague Ivan Pavlov (the same guy of “Pavlov conditionned reflex”) used this technique to study digestion (these dogs are unable to digest a meal of meat) and this work led him to 1904 Nobel Prize. Already at that time, he noticed nitrogenous injection was causing coma. However, the difficulties inherent in the determination of blood ammonia had not proved without any doubt.

In 1930, Van Caulert and Kirk published works on the tolerance of ammonia in cirrhotic patients. However, other confounding factors make this hypothesis fall into disuse for nearly 20 years. At the same time (1932), Hans Krebs and Kurt Henseleit publish their urea cycle (a set of biochemical reactions in the liver whose final products are urea and ammonia), the first metabolic cycle has been described. (Krebs, 1973)

A first clinical trial in 1948 was designed to study cirrhotic patients with a “complicated” and “uncomplicated” coma in order to come up with observations that could help treating these patients. Unfortunately, no clinical or laboratory observation allows them to distinguish the two groups, although they have identified factors, now called “precipitants”, which they propose to treat in order to avoid coma :

[liver coma arose], either spontaneously or as the result of infection, hemorrhage or sedation. Treatment, which is generally unsatisfactory, is directed at maintenance of nutrition, control of infection or hemorrhage and avoidance of sedatives.

In 1952, nearly 20 years later, another team of doctors repeated the experiments of Caulert and Kirk. Ammonia injection in patients with liver disease caused similar reactions to hepatic coma, suggesting that ammonia is involved in pathogenesis (Philips et al., 1952). Since then, ammonia has become an unavoidable factor for many researchers studying liver disease.

In 1971, the International Symposium on Ammonia Metabolism society was created. The first meeting took place in 1972 in Budapest (Hungary). The special guest was none other than Dr. Hans Krebs, 40 years after his discovery of the urea cycle (Krebs, 1973).

One of the greatest medical advances was the emergence of liver transplantation. Many attempts in 1963 by Dr. Thomas Starzl (Colorado, USA) as well as in other institutions, however the death of all patients led to a moratorium, temporarily stopping this type of surgery. Meanwhile, a great lot of research on HLA antigens has improved knowledge. Immunosuppressants made available in 1967 changed the situation, increasing for the first time survival to almost 2 years post-transplantation. In 1983, a conference of the National Institutes of Health established the medical consensus approving transplantation as a therapeutic option.

In Canada, the first liver transplant was performed by Dr. Pierre Daloze’s team in 1970 at Notre-Dame Hospital. In 2004, a first transplant with live donor was performed in CHUM. Today, in Quebec, about one hundred livers are transplanted each year (Transplant Québec statistics 2007-2016).

From portal-systemic encephalopathy (“portosystemic encephalopathy”) described by Dr. Sherlock et al in 1952, to hepatic encephalopathy a few years later, nomenclature and definition have evolved considerably over the decades. In the late 1970s, a “subclinical” form of EH was described, which was renamed in the 1990s to “minimal hepatic encephalopathy”. The term now used is “covert EH” in order to evacuate the notion that the symptoms are mild and not very disabling for affected patients. More research will be needed to establish the mechanisms leading to dysfunction of the brain in order to be able to treat the cirrhotic patients experienced the different forms of hepatic encephalopathy.

"A clinical treatise on diseases of the liver" by Dr. Frerichs, one of the first mentions of hepatic encephalopathy
"A clinical treatise on diseases of the liver" by Dr. Frerichs, one of the first mentions of hepatic encephalopathy


Gerald B. Phillips, Robert Schwartz, George J. Jr. Gabuzda, Charles S. Davidson (1952) The Syndrome of Impending Hepatic Coma in Patients with Cirrhosis of the Liver Given Certain Nitrogenous Substances. N Engl J Med, 247: 239-246. doi: 10.1056/NEJM195208142470703

Piero Amodio (2015) Hepatic Encephalopathy: Historical Remarks. J Clin Exp Hepatol, 5: S4-S6. doi: 10.1016/j.jceh.2014.12.005

Jorge Rakela, John J. Fung (2017) Thomas E. Starzl, M.D., Ph.D. (1926–2017). Hepatology, 66: 306-308. doi: 10.1002/hep.29214

Hans Krebs (1973) The discovery of the ornithine cycle of urea synthesis. Biochemical Education, 1: 19-23. doi: 10.1016/0307-4412(73)90048-4

Friedrich Theoror von Frerichs (1860) A clinical treatise on diseases of the liver. London The New Sydenham society, : 446.