Acquired liver deficiencies
Acute-on-chronic liver failure
Acute-on-chronic liver failure (ACLF) results from an acute deterioration of liver function in patients with cirrhosis, either secondary to superimposed liver injury or due to extrahepatic precipitating factors such as infection culminating in the end-organ dysfunction.
Haemophilia is an inherited bleeding disorder. The most common forms are X-linked haemophilia A and haemophilia B, caused by the inheritance of abnormal forms of Factor VIII (FVIII) and Factor IX (FIX), respectively. The severity of clinical symptoms is directly related to the coagulation activity of FVIII (<1%, severe; 1-5%, moderate; and 6-30%, mild). Approximately 60% of all cases are classified as severe.
Liver fibrosis is a chronic liver disease, whether due to viral infection, metabolic defect, toxic or autoimmune disease that causes progressive cell damage and fibrotic reaction in the liver tissue due to an excessive deposition of extracellular matrix elements and scar tissue. The physiological function of the liver progressively deteriorates and after 5 to 10 years of progressive liver fibrosis, cirrhosis appears, followed by end stage cirrhosis, liver function decompensation and eventually liver cancer.
Non-alcoholic steatohepatitis (NASH) is the most extreme form of non-alcoholic fatty liver disease (NAFLD), which is characterized by abnormal lipid accumulation in hepatocytes in the absence of alcohol abuse. The prevalence of NAFLD is estimated to reach 30% of adults in developed countries, and greater than 10% of cases evolve into progressive liver injury in the form of NASH.
Liver-based metabolic diseases
Any single enzymatic pathway plays a major role in the liver, each of them can be deficient, and each deficiency can be associated with a specific disease. Each of these diseases is rare, and incidences can be as low as 1 in 1,000,000 births. However, altogether, metabolic diseases affect one child in 900 live births. This means that, within the European Union only, 5,550 cases are newly diagnosed every year.
Many of these diseases are serious and affect severely the patient’s quality of life. Eventually, some are lethal. Few treatments are available, often with only partial effect.
The treatment under development is based on introducing healthy, functioning cells into the liver of patients suffering from severe liver diseases. The objective is to bring the missing enzyme to the patient’s liver.
Urea cycle disorders
UCD is a group of rare diseases that result from the deficiency or absence of activity of one of the enzymes of the urea cycle. Urea cycle is an endogenous metabolic pathway involved in the elimination of ammonia from the organism by converting this toxic product into urea. It consists of six enzymes: carbamoylphosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase 1 (ARG1) and the cofactor producer N-acetyl glutamate synthase (NAGS). Deficiency of one of these enzymes results into the accumulation of ammonia (hyperammonemia) and other precursor metabolites in the body, mainly glutamine, often leading to severe and irreversible brain damage due to the high neurotoxicity of ammonia.
Until now, there is no curative treatment for UCD. Patients must comply with a strict protein restriction diet and a heavy medication, including compounds that bind free ammonium to help with its elimination.
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