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|Research: Oley Research Symposium Part II: Explores Liver and Bone Disease|
Oley Research Symposium Part II: Explores Liver and Bone Disease
Most HomePEN families are only too familiar with the long shadow cast by bone and liver disease over those of our community who depend upon parenteral nutrition. Both of these diseases have been associated with parenteral nutrition therapy virtually since its inception. Although early progress was made in the study of bone disease, especially in its connection to aluminum in intravenous solutions, in other areas the disease remains a serious complication of parenteral nutrition. Little progress has been made against liver disease, and it continues to resist effective treatment. The sense that research into these disorders is now nearly at a standstill is a source of great frustration to consumers and clinicians alike. This feeling is sharpened by the knowledge that many of the resources and ideas necessary to make headway are substantially in existence, but scattered and unfocused and must be pulled together.
The Oley Foundation has taken a step to remedy this situation. Under the auspices of the American Society for Parenteral and Enteral Nutrition’s 23rd Clinical Congress, Oley sponsored a symposium on bone and liver disease for the purpose of reviewing existing research, defining priorities and developing plans of action. The discussion of liver disease was moderated by Dr. Darlene Kelly of the Mayo Clinic, and paneled by Dr. Michael Charlton of the Mayo Clinic and Dr. Alan Buchman of Northwestern University. The discussion of bone disease was moderated by Dr. Lyn Howard of the Albany Medical Center, and paneled by Dr. Dan Hurley of the Mayo Clinic and Dr. Doug Seidner of the Cleveland Clinic. Following their presentations, panelists responded to questions and comments from clinicians representing many prominent medical centers, the National Institutes of Health, and from members of industry: Coram Healthcare, Nutrishare, Inc., Sigma Tau Pharmaceuticals, PharmaThera and Cera Products. Oley gratefully acknowledges all who participated in our meeting, and extends a special thanks to ASPEN for its generous provision of facilities and support services.
A general overview of the topics discussed at the Oley symposium will be presented in two installments in the LifelineLetter. This issue covers the discussion of PN associated liver disease; the next will deal with metabolic bone disease.
What is PN associated liver disease?
Some people who require long term parenteral nutrition exhibit a build up of fat in the liver. This condition is often referred to as fatty liver, but is known clinically as hepatic steatosis. Elevated liver fat in association with elevated liver enzymes are the hallmark of hepatic steatosis as it presents in adult PN consumers. In children, however, PN associated liver disease also typically involves elevated bilirubin levels, which indicate a more severe degree of liver dysfunction. There is a growing sense among clinicians that the more severe pediatric form of PN associated liver disease has increased in frequency among adults, but no hard data is available to confirm such a trend.
In some patients, hepatic steatosis progresses beyond the build up of fat to inflammation of the liver. This condition is known as non-alcoholic steato hepatitis (NASH). Although the actual connections are not known, NASH appears to be an intermediate stage between hepatic steatosis and more serious liver fibrosis. For this reason, much of the Oley discussion centered on NASH.
NASH is not limited to people requiring parenteral nutrition. It is common as well among those who suffer from severe obesity or from type II diabetes. It is also associated with the use of certain medicinal drugs, various nutritional disorders and several other relatively uncommon medical problems. Even though these patient groups are at risk for a common liver disorder, it cannot be assumed that the disease process is the same in each case. Rather, the probability is that a number of different causes can progress to NASH. At present, however, little is known as to the natural history of the disease, that is, how it develops and progresses. Participants in the Oley symposium uniformly cited this lack of insight into the natural history of NASH as a major impediment to the treatment of the disease.
How dangerous is PN associated liver disease?
Hepatic steatosis is considered benign. That is, fatty liver is completely reversible and does not by itself seem to make people sick. Several small studies have been completed which indicate NASH, too, is a clinically mild condition, with, however, the potential to progress and evolve. The risk from NASH, in other words, is that it may lead to the onset of fibrosis, which may progress to irreversible scarring (cirrhosis) and end-stage liver disease.
The frequency with which this occurs is not known. The data that bears on the point is limited and difficult to generalize. For example, from 1993 to 1998, over ll00 people were evaluated at the Mayo Clinic in Minnesota for liver transplantation. Of these, thirty-one, or nearly three per cent were diagnosed with end-stage liver disease secondary to NASH. This figure may be deceptively small, however, due to the fact that advanced cirrhosis is typically associated with loss of fat from the liver. In other words, end stage liver disease tends to burn off excess liver fat, thereby making it difficult to diagnose NASH as the underlying cause of liver failure. With this in mind, it is noteworthy that eleven per cent of the Mayo transplant group suffered from liver cirrhosis of unknown causes. Obviously, a portion of these may have had NASH.
How is PN associated liver disease diagnosed?
The only certain means of diagnosis is by liver biopsy, that is, using a needle to collect a tiny sample of liver tissue for laboratory analysis. Because this is an invasive procedure that carries some risk, less reliable means of diagnosis are the norm.
For most patients, radiological examinations provide an acceptable alternative to biopsy. Ultra sound, CT scan, and MRI studies all reveal altered liver texture and identify the hallmarks of advanced cirrhosis. Unlike a biopsy, however, these tests do not reveal changes in the liver, such as inflammation and early fibrosis, that precede the late stages of the disease.
The least reliable means of diagnosing liver disease is through blood chemistries which measure the concentration of various liver enzymes in blood plasma. Elevated liver enzymes in the blood plasma may indicate liver dysfunction, or they may stem from other causes, while normal enzyme levels do not preclude serious liver disease. Although some patients occasionally complain of fatigue or discomfort in the area of the liver, the physical examination is generally not too helpful unless the patient is jaundiced or has an enlarged liver and spleen in which case the disease is well advanced.
How common is PN associated liver disease?
It is generally accepted that data necessary to establish the prevalence of liver disease among PN patients is not available. Despite the lack of hard numbers, it is clear that advances in PN therapy have significantly reduced the frequency of hepatic steatosis. Prior to the availability of lipids, parenteral solutions relied solely on dextrose to provide calories. In those early years, as many as two-thirds of PN consumers were believed to develop fatty liver; the contemporary figure is thought to be something between ten and fifteen percent. The prevalence of NASH in the general population has been estimated from sources that bear indirectly on the question. For example, a Canadian study in which liver biopsies were performed on approximately four hundred cadavers found NASH in roughly 21% of the sample (secondary primarily to obesity). By extrapolation of this and related figures, the prevalence of NASH among Americans works out to something between seven and twelve million individuals. Of these, it is thought that approximately one million people will develop cirrhosis. Statistical projections such as these have fostered the view that NASH has attained epidemic proportions, and have improved prospects for research support from such agencies as the National Institutes of Health.
What is the treatment for PN associated liver disease?
The standard treatment for PN associated liver disease to reduce the dextrose and lipid calories given parenterally and to encourage oral or provide enteral nutrition. The benefits of oral or enteral nutrition may be independent of a patient’s ability to absorb nutrients in the gut. In parenteral nutrition, infused nutrients go first to the heart, then to the kidneys, and last of all to the liver. This is just the reverse of a normal metabolic sequence in which the liver is first in line after the digestive tract. Although the effects of the “reversed metabolism” of intravenous nutrition are understood poorly, there is no question whatsoever that oral and enteral nutrition promote the health of the liver.
A second course of treatment commonly employed involves nutrient supplementation. It is widely suspected that the parenterally nourished liver is deficient in one or another of numerous nutrients that are critical to normal liver function. Choline, carnitine, taurine, vitamin E and glutathione are among the principal candidates for either intravenous or oral supplementation. The approach to treatment is not clear, however, because methods have not been established for assessing appropriate levels of some of these nutrients, or for doses, rates, and subsequent monitoring. One of the recurrent themes of the Oley symposium stressed the need to standardize the use of nutrient supplementation so that its impact could be measured and evaluated.
What actually causes NASH in PN consumers?
Perhaps nothing so fully, or ironically, illustrates the complex and mysterious relationship between liver disease and parenteral nutrition as its roster of possible causes. Excess dextrose or lipid calories, insufficient enteral stimulation, nutrient deficiencies and reversing the liver’s position in metabolism are a few of the potential problems that have already been mentioned. Other factors that were discussed at the Oley symposium include:
• APO B 100 is a protein that combines with fat particles in the liver to effect their removal. Both animal and human studies have shown reduced levels of APO B 100 synthesis are characteristic of NASH.
• The occurrence of liver disease in infants has been correlated to the number of days that patients receive antibiotics, as well as the number of surgeries, infections and blood transfusions.
• Small bowel resection for any reason is associated with an increased incidence of NASH.
• Under certain conditions, bacterial overgrowth from an abnormal bowel produces toxins which may damage the liver.
This list suggests some of the complexities of the problem, not the least of which is the implicit portrait of a group of patients that resists simple descriptions. PN consumers diverge widely in their medical histories. They present a large number of underlying diseases, such as Crohn’s and pseudo-obstruction. Most patients have had numerous surgeries, infections and blood transfusions. There are substantial differences in their PN formulas, their gut function and length as well as in their ability to tolerate oral nutrition. Some patients experience severe liver dysfunction after two or three years on parenteral nutrition, others go twenty years or more with no observable problem. Perhaps one day the diverse medical biographies of PN consumers will actually help to highlight a single factor or set of factors that lead to liver disease, but as things now stand, case history data are difficult to compare and connect, and this complicates the search for causes.
What’s the next step?
The Oley symposium brought to the surface the daunting array of possibilities that confronts the investigation of PN associated liver disease. Yet participants agreed nearly unanimously that the next step is reasonably clear and relatively simple; namely, to establish standards for testing and treating liver disease that will create comparable data bases from one clinical program to another. A symposium workgroup, formed to explore just what such standards might entail, completed a rough outline of key areas of concern, ranging from tracking a patient’s PN formula changes to achieving uniform protocols on nutrient supplementation. The short term goal is to develop this material into testing and treatment procedures that will enable medical centers to accumulate data in a way that illuminates central research questions; questions about the prevalence of hepatic steatosis, for example, its natural history, or the existence of PN subgroups that are at greater or lesser risk of the disease. Answers to these questions would in turn support more narrowly focused, treatment-oriented studies.
The process begun at the Oley symposium is ongoing, and consumers may rely on the LifelineLetter to report on all developments. It is especially important that PN consumers remain abreast of this project so they might thoroughly consider their own next step. Certainly, no group has more at stake, and quite possibly none can do more to generate momentum for collaborative research into hepatic steatosis. It is not too soon for consumers to acquaint their nutrition support providers with the Oley initiative, and to discuss with them the possibility of participating in standardized, multicenter studies of PN associated liver disease. This is not to suggest that any such study is presently in the offing, but rather how consumers might help keep the spotlight on research. The clinicians who joined with Oley to share their perspectives on researching PN associated liver disease, recognize they were addressing their thoughts to the larger community of homePEN consumers and providers. It is an invitation for consumers, too, to join the dialogue, both to convey their interests to their physicians and to encourage their home infusion providers to consider how they might contribute to a collaborative research strategy against PN associated liver disease.
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