Originally we doctors thought that fatty liver was not a disease and had no consequences for liver function. In retrospect, these can be said to be naive considering them as massive structural changes that may happen to the liver. However, indirect evidence was piling up indicating that hepatocytes with fat in them are not fully functional. As an example, there is a high rate of primary non-function of fatty liver grafts at liver transplantation. Also, epidemiological evidence showed that fatty liver is indeed a disease in the sense that it makes people's prognosis worse. These fueled new interest in what may be wrong with the fatty liver's function. Now, describing the function of the liver is not so easy because the organ has numerous metabolic functions and many of them cannot be measured in quantitative terms because they are part of complex interactions. Therefore, in my lab, which shows a number of functions the liver takes care of. Functions that are only in the liver, functions that can be quantitated by established methods in humans and functions that represent different hepatocyte compartments. We chose the galactose elimination capacity, the urea synthesis capacity, the aminopyrine clearance, and the biliary excretion of indocyanine green. The galactose elimination capacity, the GEC, runs in the cytosol by enzymes that are preformed from fetal life and are not influenced by induction by substances, or regulated by hormones. The GEC is strongly associated with short and long term prognosis in acute and chronic liver disease. The urea synthesis capacity is quantified by the Functional Hepatic Nitrogen Clearance, the FHNC. Running on the urea cycle involves both mitochondria and cytosol. The enzymes are very old in the origin of species and survival is not possible without urea synthesis. The process takes up a key position in whole- body nitrogen balance. The aminopyrine clearance, the AP-CL, runs in the endoplasmic reticulum by the cytochrome P450 enzyme family, that is important for our elimination of toxins and xenobiotics, including drugs. That clearance of indocyanine green ICG-CL is taken care of by the bile acid transporters located on the membranes, where hepatocyte meets hepatocyte. These transporters concentrates substances out into the bile. It is a measure or the excretory function of the liver. We performed these forward tests in patients with different degrees of metabolic fatty liver disease and in relevant control patterns. We thereby constructed a functional mapping of the fatty liver hepatocyte. The results are shown here. The GEC compared to control was increased by one-fifth in the fatty liver patients. This was very surprising because it seems to be an improvement over healthy. It proved to be caused by the fact that the patients had much larger livers and this liver function seems to follow liver size more than body size. However, still a liver size increased much more than did their GEC. There is more to the story, that is, part of the fatty liver must be less functional. Therefore, we did Galactose Isotope Positron Emission Tomography scans, also called PET scans. This method gives true time in vivo measurements of galactose metabolism and thus liver function in local areas of the liver. Here you see a PET scan of a normal person. The more red, the more active the function. Note that the normal liver is functional, homogeneous, so that all parts of it are equally good. Such a normal person can be compared with a person with fatty liver disease. It is evident that the fatty liver has less function in many liver areas and it is also evident that the liver function becomes variable from one area of the liver to another. In this way, the liver function in the fatty liver is highly heterogeneous. This is a marked functional structural disturbance of the liver that is otherwise seen only in patients with frank cirrhosis, which the fatty liver patients did not have. The next liver function, we looked at was urea synthesis measured by the FHNC. As can be seen, there was a marked reduction in FHNC in the fatty liver patients. This was a confirmation in humans of our original findings from breaths with diet induced fatty liver. It is a very important finding because urea synthesis takes up the central regulatory role in the body's nitrogen homeostasis and balance. When urea synthesis goes down, the substances that drive it accumulate. This is the case for the toxic ammonia that is generated by all amino acid metabolism in the body and which hands central brain functions. As seen in patients with liver failure as hepatic encephalopathy. Fatty liver disease patients tend to have higher than normal ammonia and also a brain function deficit incognition. High ammonia in the liver has a sort of paracrine effect and activates the liver's stellate cells, which promotes fibrogenesis and thus the progression of fatty liver to steatohepatitis and ultimately cirrhosis. Likewise, the damage to urea synthesis makes amino acids in blood accumulate, which stimulates glucagon release so much that the glucagon receptors get exhausted, leading to glucagon resistance, which will play a part in the patient's risk for developing diabetes. The cause is found in animals. We have shown that the hepatocyte fat disturbs the mitochondria so that the mitochondrial urea cycle genes become damaged by hypermethylation of their promoter regions. Likewise, we have shown in humans that fatty liver inhibits the expression of the whole chain of genes governing hepatic nitrogen conversion, including amino acid transporters, glucagon receptors and urea genes. The damage to the urea cycle is a real problem in human fatty liver diseases and is involved both in the symptoms of the disease and in the disease progression towards cirrhosis. We looked at the patient's livers ability to metabolize drug by their amino (inaduible) clearance. This liver function was markedly decreased, which is important for dosing of drugs and for the patients defenses against toxic effects of xenobiotics. The patients are well less protected against toxins and side effects to drugs. Finally, we looked at the fatty liver patients liver excretory function to the bile. This was measured by the indocyanine green clearance. As can be seen, this important liver function was not affected by fatty liver. Bile formation can therefore be taken to be normal. There may be an interplay between bile acid and fat metabolism in fatty liver diseases but these seems not to involve problems with bile acid excretion by the liver. We have shown that a fatty liver is not a functionally healthy liver. The effects of the liver fat on liver functions are dissociated among compartments of the hepatocyte and between functions, so that some functions are badly damaged others less so and some remain normal. This has consequences for the disease cause and for the patient's general health. These functional problems should be taken into account in the clinical management of the patients. The fact that the fatty liver does not work as well as normal, very much stresses the need for getting rid of liver fat. It should be kept in mind that even moderate weight loss efficiently de-fattens the liver.
