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New Hope for PBC Liver Disease

Primary biliary cirrhosis, or PBC is a slow acting liver disease that can lead to scarring and the need for a liver transplant.  PBC affects 10 times as many women than men and is not related to drinking alcohol. While there is no cure, a promising new treatment could slow its progress.

For Linie Moore, Barbie dolls are a welcome escape from a devastating diagnosis that's left her tired and itching all the time.

"I itch so bad that at times it feels like little bugs are crawling on you," Linie Moore told Ivanhoe.

First diagnosed with primary biliary cirrhosis or PBC twenty years ago, she was told to prepare for a liver transplant.

"And I have a son that had just gotten into high school that I was worried about being without a mother," said Moore.

Doctor John Vierling says most patients take a daily dose of urso, a bile acid that improves the liver's ability to function. But not everyone responds. Now there's a new treatment known as obeticholic acid that could help.

"We are going to have a therapy where we can really prevent the progression of this disease," John Vierling, M.D., and Chief of Hepatology at Baylor College of Medicine told Ivanhoe.

It's the first new therapy in 20 years.

"Everything that pertained to liver test and function improved," said Dr. Vierling.

Welcome news for Linie and the more than three-thousand members of the support group she started.

"PBC is not a death sentence," Moore explained.

To learn more about Linie's PBC support group, log onto pbcers.org or find the PBC-ers on Facebook. Since PBC is not caused by drinking alcohol. Linie's group and the medical community are pushing for a new name, primary biliary cholangitis, to fight the stigma attached to the word cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is a disease that slowly destroys the bile ducts in the liver; this can cause harmful buildup in the liver and severe, irreversible scarring. Bile plays a role in digestion and removing cholesterol, toxins and worn-out red blood cells from the body. Although the direct cause is unclear, PBC is considered an autoimmune disease in which the body turns against its own cells. When T cells build up in the liver they can cause inflammation that spreads and damages liver cells which are then replaced with scar tissue. Cirrhosis is considered scarring of the liver tissue that hinders the liver from performing essential functions.

(Source: http://www.mayoclinic.org/diseases-conditions/primary-biliary-cirrhosis, http://www.mayoclinic.org/diseases-conditions/primary-biliary-cirrhosis/basics/causes/con-2002937)

TREATMENT: Since PBC has no unique symptoms, diagnosis typically comes from abnormal results from blood tests. No direct cure exists for PBC; however a standard medication for treatment is ursodiol, an urseodeoxycholic acid (UDCA) which is a naturally occurring bile. The drug extends life expectancy and may delay the need for a liver transplant. If drug treatments are ineffective and the liver begins to fail, a liver transplant from a healthy donor may be required. Fatigue and itching are common symptoms of PBC and can be treated with modafinil (Provigil) and cholestyramine (Locholest, Prevalite), respectively.

(Source: http://www.liverfoundation.org/abouttheliver/info/pbc/, http://www.mayoclinic.org/diseases-conditions/primary-biliary-cirrhosis/basics/treatment)

NEW TREATMENT DRUG: Although UDCA is the standard treatment for PBC, 50-percent of patients show no adequate response for improvement. The newest treatment, obeticholic acid, is showing improved levels of biomarkers that correlate with a reduction in the risk for a liver transplant. Obeticholic acid is chemically similar to UDCA, but it is an agonist to farnesoid X receptors (bile receptors). The goal of the phase three trial of the drug is to improve liver function, thereby avoiding the need for a liver transplant or other clinical procedures.  Currently, the study is on-going, but not recruiting new participants. For more information on the clinical trials, visit: http://clinicaltrials.gov/show/NCT01473524.

(Source: http://www.medscape.com/viewarticle/823669, http://www.medpagetoday.com/MeetingCoverage/EASL/45237)

FOR MORE INFORMATION ON THIS REPORT, PLEASE CONTACT:

Graciela Gutierrez

Baylor College of Medicine

(713) 798-4710

ggutierr@bcm.edu

If this story or any other Ivanhoe story has impacted your life or prompted you or someone you know to seek or change treatments, please let us know by contacting Marjorie Bekaert Thomas at mthomas@ivanhoe.com

John Vierling, M.D., Professor of Medicine and Surgery, and Chief of Hepatology at Baylor College of Medicine discusses NASH and PBC liver diseases.

Interview conducted by Ivanhoe Broadcast News in September 2014.

 

We are talking about NASH which really starts out as fatty liver disease. Can you talk about fatty liver disease and how it transitions into NASH and what that is exactly?

Dr. Vierling:  Fatty liver disease can be caused by a variety of things such as excessive alcohol. Another cause is the metabolic syndrome which is increasingly common worldwide, particularly in this country and countries that have access to food and are becoming increasingly obese. Several medications can also cause fatty liver. But if we concentrate on the nonalcoholic fatty liver disease which is caused by obesity, pre-diabetes or diabetes, high cholesterol or triglyceride with or without other manifestations such as hypertension or hyperuricemia and gout, referred to as the metabolic syndrome, we have a huge problem. If we look at nonalcoholic fatty liver disease it's being subdivided into those that have fat only in their liver and fat in Greek is steatosis, so this is called hepatic steatosis. It is a benign form of nonalcoholic fatty liver disease. However a minority of people have in addition to steatosis inflammation of the liver. That is called nonalcoholic steato, meaning fat, hepatitis; the Greek word meaning inflammation of the liver or nonalcoholic steatal hepatitis, NASH for short. NASH because of inflammation can go through the process of wound healing. When any of us have had inflammation we know that as our body heals that site of inflammation, say a boil on your skin that it will do so by forming scar tissue. Scar tissue and inflammation go hand-in-hand -- that makes NASH a progressive liver disease that can lead to progressive fibrosis or scarring of the liver and ultimately cirrhosis. When a person has cirrhosis that processes then can progress to liver failure and risk of a hepatocellular carcinoma a primary liver cancer and the need life-saving liver transplant to prevent premature death. So, NASH is not a benign entity. Now to put some numbers with that we think that in U.S. now somewhere over forty-million Americans have nonalcoholic fatty liver disease. We know that there is an estimate of greater than twenty-million Americans that may have NASH. Those are very frightening numbers especially if we look at what would be the consequence of people with NASH progressing to cirrhosis and ultimately needing a liver transplant. Last year in this country we did approximately sixty-six hundred liver transplants for all causes; and liver transplantation worldwide has been dominated by the indication of chronic hepatitis C infection. In the United States we estimate that four-million Americans have hepatitis C. They've have been the dominate indication for transplantation over the past few decades. Just imagine what it would be like if twenty-million Americans were to proceed to cirrhosis. It would overwhelm our health care system, and liver transplantations as the means of saving lives would be totally inadequate. This is a real call to action. This is not just in the United States this is happening worldwide and it is a problem that has to be confronted.

Why you think these numbers are exploding?

Dr. Vierling: They're exploding because they're driven by access to food in an ever-changing society and culture and workplace the no longer expends a lot of calories to do the daily work. We have an obesity phenomenon which is well documented in our country and in other industrialized countries that are not considered developing countries. With that comes the risk of maturity onset or type II adult diabetes and with those two come the risk of high lipids. This overall metabolic syndrome, a phenomenon of middle aged and older, is something that is now increased in its incidence and it's prevalence throughout our country. Just look around at the mall and you see this in action; look at a movie made in the 1950s and a movie made now and what's in the background or even the size of the actors and actresses in our modern movies. These things are changing in our society and that's the major cause in a nutshell. Now it's not just limited unfortunately to adults. We now have children that are obese in increasing numbers extraordinary compromised. They get the maturity onset diabetes by the age of ten. There are many children in Houston and elsewhere between the ages of ten and fifteen that already have cirrhosis through the NASH. This is almost out of control.

It sounds like it really all boils down to diet.

Dr. Vierling: Certainly obesity is the major risk factor and we know that if a person with nonalcoholic fatty liver disease were to lose ten-percent of their starting body weight that it would have an enormously positive impact on the liver. Reducing the fat and inflammation by ninety-five to ninety-nine percent, just ten-percent and that can be almost any starting weight. If somebody who is three hundred pounds were to lose ten percent, thirty pounds they would still would weigh two hundred and seventy pounds, but they would have benefitted their liver. The first ten-percent of body weight disproportionately affects the fat that is around our internal organs within our abdomen. We collectively call our organs viscera, so we call that visceral fat. That hormonally active fat is making substances that go directly in the bloodstream to the liver that cause the liver to become fatty; and in the minority with NASH to develop inflammation in addition to fat. If you knock out that visceral fat you've made your first step. Now it's also known that if you were to lose twenty-percent of your starting body weight and to keep that weight off permanently that would you would not suffer long-term adverse consequences of nonalcoholic fatty liver disease. It's generated by weight and its relationship to diabetes, and lipids the so-called metabolic syndrome. But it can be controlled most appropriately by weight reduction. The weight loss doesn't have to be down to lean body weight to be effective.

That will allow the liver to regenerate itself?

Dr. Vierling: The liver will lose the fat and the swelling and the liver cells will resume normal function. By losing the fat there's no longer a mechanism attracting inflammation of the liver because it's not an infectious disease that the immune system and the white blood cells are fighting. It's a response to the presence of the fat. Get rid of the fat get rid of the inflammation and you quiet the disease. The liver has enormous regenerative capacity, enormous functional reserve.

Why do we get to the point where we need to have liver transplant, when our livers are able to regenerate themselves. Is it just because of that constant stimulus?

Dr. Vierling: That's an incredibly important question and that gets us to a number of issues that is distilled into a single word: cirrhosis. Cirrhosis of the liver is defined as diffuse scarring which then by entrapment of islands of liver cells stimulates those liver cells to divide, to regenerate. The liver is a regenerative organ. As cells regenerate in three dimensions, it will form a nodule. Now as that nodule is forming and pushes against scar you end up with nodules of regenerating cells encapsulated in scar. You can think of the liver in that as if it were a bag that you filled with marbles. Each of the marbles one of these regenerate nodules covered with scar. The liver in cirrhosis is a great example of regeneration but it is regenerating in a way with that scar impedes blood flow and the functions of the cells that is consistently want to divide maintaining that nodularity and so it's ineffective in its regeneration, it becomes a disease process unto itself. It's the common single pathway in which many different diseases viral hepatitis, autoimmune liver diseases, metabolic liver diseases such as fatty liver, drug induced liver diseases that are chronic and then finally genetic diseases all spiral into cirrhosis. Cirrhosis does regenerate a normal liver because encapsulating that regeneration within scars results in an abnormal liver.

Besides shedding weight up to this point there hasn't been a treatment.

Dr. Vierling: That's been true. There have been a number of trials of treatment and some are encouraging based on hypothesis driven research. Regarding weight loss which is definitely substantiated in all studies that have looked at weight loss including bariatric surgery with major weight loss for morbid obesity confirming the positive impact of weight loss. If we look then to drug therapies we know that the first therapeutic approaches were to use medicines that helped countermand the overshoot of insulin that occurs in people who are obese and either pre-diabetic or overtly diabetic. That overshoot is called hyperinsulinemia. Hyperinsulinemia is a root cause of nonalcoholic fatty liver disease. Using medicines that combat hyperinsulinemia, we found that they could influence fatty liver. The one that was studied most in adults has been pioglitazone. Pioglitazone was used in a study in which there was a comparator that had come from original trials done in children using vitamin E as an antioxidant to suppress inflammation and the stress within the cell that contains the fat. To everyone's surprise this NIH sponsored trial called the PIVENS study showed superiority of vitamin E over pioglitazone. Well pioglitazone does some positive things the unfortunate side effect of its use is that it takes fat out of the liver and causes people to deposit fat in their periphery.  Most people don't like the cosmetic effect of weight gain and excessive adiposity around their abdomen or their hips or buttocks. Vitamin E was beneficial but it was only beneficial in forty-three percent of the patients. No one knows how to actually predict which patients will benefit.  There have been studies using metformin, studies of a variety of antioxidants and the field keeps fluidly moving forward. In clinical trials there are several different approaches but the most profound approach in terms of success to date has been the studies of obeticholic acid which is a farnesoid X agonist. This particular nuclear receptor when it is stimulated by the modified human bile acid has a multitude of effects. What we know is that in the NIH sponsored trial of an obeticholic acid had a planned interim analysis halfway into the study. Those treated with obeticholic acid had benefitted so much compared to controls that the data safety management board stopped the trial after the halfway analysis. Other trials in the field include PPAR Delta agents those are moving in to Phase III. There are approaches that don't try to influence fat within the liver but combat the scarring that would lead to cirrhosis using specific monoclonal antibodies that are injected to block the formation of new scar. There are studies about ready to start that block cell wall constituents of the bacteria within the gut that may influence then the ultimate expression of disease. The role of gut bacteria has had much press recently because of the magnitude of our bacterial flora. It is interesting to speculate as to who's who in this room because each of us have four hundred million cells in our body but bacteria as single cells in our body outnumber us. They number in the seven hundred to eight hundred million range. Are we really the home of the bacteria or vice versa?  They outnumber us quantitatively two to three to one. Those bacteria are playing roles in human diseases.  We know in mouse studies that if litter mates are fed different diets, one group can become obese.  If you transfer the bacteria from that group's gut into the gut of the lean mice they will become obese. It's really influencing how we eat and how we are satisfied with what we eat. There's like an enormous playground for scientists to identify potential therapeutic targets.

Could fecal transplants help?

Dr. Vierling: People have done that as you probably are aware for treatment clostridium difficile when it is overwhelming and recurrent, causing clinical problems and that does work. Whether you know a transplant of bacteria from a lean person's guts in to an overt obese persons gut would work would largely depend on whether the obese person changed their diet because it was the diet that changed the flora in the first place. And the flora that is developing over time with people that become obese is a flora that could recur in a normal flora if you keep giving it signals from the diet that caused originally the change. If you transplant it and you stop the dietary insults and kept the normal flora you probably would remain lean. But that's like saying that the person ate a diet that would have caused them not to become obese in the first place. Thus, we're right back to the importance of weight loss. It's probably more appealing to someone to lose weight than to have fecal transplants.

Getting back to the Flint trial, can you talk about what is the mechanism that allows the OCA to work?

Dr. Vierling: Well that is an extraordinarily important and still unanswerable question right now. We know that the agonist of FXR obeticholic acid can have protean effects. This agonisim in other pathways related to basic metabolic pathways including gluconeogenesis and metabolic events. You know what combination of these events then transpires to reduce fat and the inflammation is the end point of the analysis and the positive impact is difficult to fully understand. In the control group and the treated group there were no major differences in the diet that they had or the amount of the groups' weight change while in the study. This wasn't sort of the group being treated suddenly lost a tremendous amount of weight and that there was a weight-based explanation. But the mechanisms need to be further scrutinized because within them are likely to help identify additional targets for people to develop future therapeutics

Is it fair to say that it's almost like a synthetic bile?

Dr. Vierling: It is a modified bile acid. Bile acids are made by liver cells and in human beings the dominant bile acid is chenodeoxycholic acid. Obeteiholic acid is a modified chenodeoxycholic acid. Why chenodeoxycholic acid? The farnesoid X nuclear receptor FXR was shown to have as its principle hormonal stimulant chenodeoxycholic acid. When you modify this and create the molecule known as obeticholic acid you increase its capacity to stimulate FXR a hundred fold. What you could get in nature would be one while what you can get with obeticholic acid stimulation of the receptor is a hundred. It's that driving force that intensifies all these pathways because a nuclear receptor once it gets in the nucleus then influences the expression of genes, and it's the increased expression of genes which create proteins that signal and create the environment that changes within the cell.  This causes a number of effects, it is anti-inflammatory, and it obviously has metabolic consequences as we're seeing in this Flint study. The modification of a natural bile acid allowed us to drive stimulation of the farnesoid X nuclear receptor and all the genes that it stimulates.

How big of a breakthrough would you say this is?

Dr. Vierling: I think that it's always a breakthrough that you have something that is so powerfully beneficial that your best estimates of how long you would need to study it were twice as long to show effectiveness. Having stopped prematurely because of efficacy is unusual.   Usually what stops a study prematurely is poor safety or tolerability. I think this means that the impact of the primary and the secondary endpoints was so significant that it could be seen in half the time that was proposed. Yes, this is a very significant finding. Where it's going to fit in our armamentarium requires more information. We had a prior study that has been published. This was done in patients with diabetes and obeticholic acid. In that study and the flint study, one saw some changes in lipids that we need to understand further.  Specifically a rise in total cholesterol and reduction in the high density lipoprotein fraction of cholesterol which is the so-called good cholesterol fraction. That's been seen not only in those studies of diabetes or NAFLD, but the that same pattern was seen in studies of the autoimmune disease primary biliary cirrhosis. It is fair to say that obeticholic acid changes cholesterol metabolism in that way. What is the clinical consequence becomes the question were you to be using the drug long-term. The answer is we don't know because it has not been used long-term. However, it is obvious that we deal with high cholesterol and a reduced HDL medically with a class of drugs called statins. Statins would be available to combat that change if it had clinical consequences. But we need to know more details and further studies will shed light.

Were there any short term side effects?

Dr. Vierling: Short term side effects in both groups were very modest. You're dealing with long-term studies and you must report everything that went on, you're always going to find background noise. If everyone here were asked to keep a little diary for the next six months we're probably going to have a bout of nausea and maybe a bout of diarrhea, a headache or two and a sore muscle, various things. This is the type of thing that one finds in these reports and I think they're more background noise rather than signals of toxicity.

Are you able to talk about a few of the other diseases that are being looked at and treated with this yet?

Dr. Vierling: Well there are a number of potentials, but I think that the one that really stands out for us is the positive studies that have occurred in the disease called primary biliary cirrhosis. This particular disease, PBC for short, is a prototypic autoimmune liver disease. It's predominantly a disease of women; about ten to eleven women for every one man, tends to be diagnosed in middle age and tends to be progressive in those that do not respond to a different form of bile acid therapy which is the naturally occurring bile acid ursodeoxycholic acid which we call URSO for short. Patients who respond well to URSO by reducing significantly their abnormal liver test numbers have an excellent long-term prognosis. In fact, you can have certain levels of reduction where you can virtually guarantee if a patient achieves that, that they won't progress or need a liver transplant. However, not everyone responds to URSO and in those that don't respond, obeticholic acid was shown to ameliorate not only the abnormal enzymes but virtually all other measures. Those included inflammation markers. This gives us hope that we're going to have a therapy that either alone or when added to URSO in those that are not responding on the basis of their individuality will prevent a progression of this disease. Now we keep talking about the prevention of cirrhosis and we've already talked a bit about the definition of cirrhosis. While the name primary biliary cirrhosis clearly would suggest that everyone with the disease already has cirrhosis, it really is a misnomer because the vast majority of people at the time of diagnosis do not have cirrhosis. They are at risk of progressing to cirrhosis if left untreated but they don't yet have cirrhosis. And because of that, they're at a real disadvantage in a number of ways. Number one, the psychological impact of somebody telling you that the name of your disease has cirrhosis might make you immediately assume you must have cirrhosis, which you and others may have false connotations about. Then you also have the issue of having the inability to communicate freely; you're a little hesitant to tell people you have a disease with the word cirrhosis in it. Try to fund raise for a disease with cirrhosis in the name.  It again raises the connotations that reflect general societal ignorance about the word. It's not unusual for people to equate cirrhosis with advanced alcoholic liver disease. It even happens in children who have pediatric and developmental and genetic diseases and you'll find neighbors saying, well I never knew that six-year-old was alcoholic. It's a bizarre kind of thinking process. This disadvantage is hopefully going to be overcome by a worldwide effort to change the name officially to primary biliary cholangitis. That would retain the abbreviation PBC which has been embedded in the literature and in medical terminology, but get rid of the word cirrhosis to help these individuals. The people with PBC do not necessarily have cirrhosis. But it's not to say that therapies like obeticholic acid and ursodeoxy cholic acid are not effective for those who actually do have cirrhosis caused by PBC, they actually are effective. I think that gives us hope that we can ultimately retard, either by preventing progression to cirrhosis or for those with cirrhosis by preventing further progression so they do not need a liver transplant.

It's interesting because the patient that were speaking to about PBC was saying how even some of the medical professionals assumed that she was an alcoholic.

Dr. Vierling: If this is again a societal issue; and just because one is in the medical field it doesn't overcome a societal ignorance about the liver and especially about the term cirrhosis. Most people have heard cirrhosis in a lay context and they assume that it is highly specific for whatever that context was and statistically that may have been with someone with alcoholic liver disease that was said to be the person with cirrhosis. They don't understand that cirrhosis is a final common pathway for virtually all chronic liver diseases. Each will come down that pathway so cirrhosis really can be caused literally by hundreds of different root causes. It is itself a process, once you have cirrhosis it's not a terminal event at that moment when has just developed, nodularity and scar being its definition. It's the progression that is the problem, which is when your disease further kills cells and replaces those functional cells in the liver with nonfunctioning scar tissue. Basically it whittles away the functional mass of the liver and that deterioration is what causes the risk of complications of cirrhosis and the ultimate potential need for liver transplant. If you have cirrhosis and you stop the killing of cells you will lock-in that level of hepatic function. Instead of a deteriorating path downward you're going to lock it in at a higher level. If you catch it early on, you can have long-term success, good quality of life. But the trick is to catch cirrhosis early no matter what the root cause may be.

How common is PBC?

Dr. Vierling: It's a relatively uncommon disease; I wouldn't consider it rare; it's been demographically looked at.

You would or would not?

Dr. Vierling: Would not. It's uncommon, but not rare. Let's say that when you're looking in the United States you're probably looking somewhere in the two hundred fifty to eight hundred thousand range. The demographics in the United State and Europe are a little bit different. Our information in the United States doesn't come from any national databases and that's one of the problems. We can find some people to put in the numerator; the question is how many people are in the denominator. I'd say that it's not uncommonly diagnosed but it is not exceedingly rare. In general practices of gastroenterology throughout the world, practitioners are likely to have one or several patients with this disease in their private practice.

It typically affects women though?

Dr. Vierling: About ten to eleven for every one man. It's not exclusively women but it's dominated.

Is there a hormonal component to it?

Dr. Vierling: Well we really believe that the female predominance must mean that there is something hormonal. Exactly what that means however has not been fully understood. We know that the disease tends not to be diagnosed in children prior to puberty. The onset of the earliest diagnoses tends to be in the late teenage years and some of those have even been debated as to whether they're accurate diagnoses. This makes PBC unique among autoimmune diseases which tend to always have childhood forms this apparently does not. We don't know why that may be. That suggests that in addition to female sex it has to do with the changes of puberty and the influence of those hormones. We could also look at it in a way that maybe men have some protection afforded by the Y chromosome and its products which are obviously absent in women and so maybe it's like a permissive environment to be female and is more protective to be male. But we really haven't figured this out because the nature of the disease has not allowed us to understand exactly what may trigger it. We know a lot more about the mechanisms then we do the triggers. But the triggering must be there because it has an onset and it's rare enough that the trigger which we believe may be environmental or could be infectious, might be more prevalent than the tiny minority that react at that particular time of exposure. There are issues about the triggering events, there are issues about genes including the genes that are associated with male and female sex and then there's the issue of timing. I think several different things need to occur within a short period of time to get disease. If they don't occur in that period of time even though you might be susceptible to disease you won't get it.

I've heard from some that they would consider PBC a death sentence. Is it a death sentence?

Dr. Vierling: PBC, which I'm hopeful will be known in the future as primary biliary cholangitis, not biliary cirrhosis, is not a death sentence. In fact on the contrary, we know that after the introduction of ursodeoxycholic acid treatment with its ease of use and great tolerability, that when the diagnosis was made that patient was prescribed URSO as long-term therapy. Now in that context we could look over a number of databases and in the United States in particular we can see that the rates of death due to liver failure in patients with PBC have declined over the past two decades. That's not just better care because there's another cholestatic adult liver disease called primary sclerosing cholangitis or PSC; and PSC has remained with the same death rate throughout that period of time when PBC has declined in the death rate. If you look at the number of hospitalizations, length of hospitalizations, and the numbers of transplants done for the indication of PBC, all of those things have fallen. If you look at the national databases in Europe where they have sort of a cradle-to-grave healthcare analytics, you find the patients with PBC that got URSO and had excellent responses where all their enzymes fell did as well as a comparative group normal women of the same age who were followed to determine actuarial survival. They did not end up with cirrhosis, liver failure and death. The people that don't respond well to URSO have a decreased life expectancy and an increased probability of liver transplant. But treatments with drugs, such as obeticholic acid may make bad outcomes a thing of the past.  So PBC is far from a death sentence.  It's actually a disease that we have the ability to treat right now but only a subgroup respond to that treatment and thus we need better treatments for everyone.

The subgroups are in danger unless they had treatment?

Dr. Vierling: That's correct.

What's the clinical trial status the PBC? What are some of the results to date?

Dr. Vierling: Obeticholic acid now is in Phase III trial which is the FDA phase that would lead were the results positive and the drug to be safe to actual FDA approval in the marketplace. They are in Phase III because of the positive results that were seen in the Phase II study obeticholic acid in patients with primary biliary cholangitis, not cirrhosis. Those trial results showed that obeticholic acid substantially decreased the serum level of an enzyme called alkaline phosphatase. This is one of the key enzymes because in all of these prior studies we talked about being from the databases in Europe, a fall in alkaline phosphatase was the most meaningful predictor of your long-term outcome in those that responded to ursodeoxycholic acid. When you're looking at the response to URSO in one of the models which is a model of Perez, a Spanish model, which would portend a good outcome long-term on ursodeoxycholic acid.  Obeticholic acid at multiple doses caused a fall of alkaline phosphatase greater than forty-five percent in virtually everybody. In addition, the AST and ALT enzymes which are leaked from injured hepatocytes were significantly reduced. Gamma-glutamyl-transferase another enzyme associated with hepatobiliary damage was also reduced. Very importantly there were reductions in the markers for overall systemic total body inflammation. That of course positive changes in the liver one of the largest organs in the body and the site of intensive inflammation in PBC. You look across the board at all of these positive factors. Everything that pertained to liver test in function improved. In the study there were changes in lipids that we discussed earlier. A slight rise in total cholesterol and a slight reduction in the high density lipoprotein or so called good cholesterol. But there are no adverse events noted within the study itself because of those cholesterol abnormalities. We know that, that has again happened in the Flint study, it happened in the study of diabetes and it appears to be a drug effect. With longer term follow up we'll know more about it and whether it does or does not need any kind of clinical treatment because it would be treatable. When we look at the Phase II study we also know that there was a dose relationship in terms of the toxicity of pruritus, or itching, in PBC that was not the seen in the Flint Study. Itching in patients with PBC and other forms of adult as well as pediatric cholestatic liver diseases is a significant side effect to be contended with and it is a primary symptom in of these diseases. What we found in the PBC study is that patients prone to itch experienced itch in a dose related manner. This allowed a dose that was quite efficacious based biochemical responses to be selected without the risk of itching associated with the higher doses. We're excited that this is in Phase III, it's the only such Phase III study in this disease that has been conducted in the last four decades since the original studies first of ursodeoxycholic acid.

Is itching then that's indicated for both NASH and PBC?

Dr. Vierling: No.

Just PBC.

Dr. Vierling: It was only observed in patients with PBC.

Are there any other symptoms for that?

Dr. Vierling: Generally no. They've been well tolerated as I mentioned in the Flint study and the other side effects were extremely mild.

As far as symptoms, was there fatigue?

Dr. Vierling: If we look at PBC as a disease, its dominant symptom fatigue. That fatigue is in some ways unique and in other ways expected. What's expected about the fatigue is that PBC is an inflammatory disease and the liver is the second largest organ after your gut.  In PBC the liver holds an intense concentration of inflammation. When you have inflammation you end up with all sorts of protein products shed in to the circulation that can cause fatigue. We've known this since we had chronic inflammatory diseases through our human history, like chronic tuberculosis, inflammatory bowel disease, rheumatoid arthritis and various things that people had no therapies for, and fatigue was always a major part of them. We also know that when people are treated with PBC have an effective response of treatment that the fatigue lessens. The part that is less clear is other manifestations of fatigue they've been studied as surrogates for depression, surrogates for lack of sleep, surrogates for other things that might contribute to fatigue and they haven't panned out that those are the explanations. There appears to be something about the fatigue that we still can't yet define and hope to because defining it would allow therapeutic options for it. But that's the dominant symptom in this disease. Pruritus or itching is another symptom and it can be one of the very earliest symptoms.  If a person progresses to advanced cirrhosis the itching tends to lessen and sometimes just spontaneously clears.  It tends to occur earlier in the disease, and not as much later in the disease. The disease is associated with several other autoimmune diseases each of one of which may cause the patient to have symptoms. Among them is thyroiditis leading to hypothyroidism. Of course if you're hypothyroid then you may be fatigued also. It is a key point that everyone with PBC and fatigue needs to have thyroid function checked to be sure that it's not due in part to treatable hypothyroidism. You also tend to have symptoms of dry eye and dry mouth which have cumbersome names of keratoconjunctivitis sicca and Xerostomia respectively. They are part of what is known as the Sjogren's syndrome. They occur much more frequently in patients with PBC although they're a bona fide stand-alone autoimmune disease. Scleroderma is another autoimmune disease that is associated with PBC. PBC patients, because of the cholestasis and in part because of the female sex, have a risk for demineralization of the bone. And they have a higher than expected frequency of osteoporosis of the bone which can lead to a variety of symptoms particularly if there are compression fractures or spontaneous fractures of the bone. When we look at this sort of overlay it's important for clinicians to perform liver tests on any patient with Sjogren's syndrome, scleroderma, keratoconjunctivitis sicca or hypothyroidism., Because these other things that brought them to the attention of the doctor may have been associated diseases accompanying PBC.

Since this is a rare but not uncommon disease, how is that a challenge for medical professionals since not many people know about it; the awareness in the medical community as well as the challenge for patients?

Dr. Vierling: PBC is as we said uncommon but not rare, and I mentioned that in specialty practices of gastroenterology and hepatology virtually every practice has one or several patients with that diagnosis. Yet the overall medical community of general practitioners is they internists or family practitioners, are usually less informed about this particular disease. This cuts across other medical specialties. An illustration of that would be the not uncommon story of a woman who develops itching. We would immediately be looking at liver tests and immediately be thinking about cholestasis. That person may start out with a general practitioner for several weeks or months with some antihistamines.  Next they may be sent to the dermatologist who may do a skin biopsy and find no pathology because there's no rash.  They can't understand why they're itching. They may see someone else and occasionally might even see a hematologist because iron overload can cause itching. Down the line they come until ultimately someone says, by the way there's a liver panel that we've just got and it's abnormal maybe we'll send them to a gastroenterologist or a hepatologist. That is something that was encountered fifty years ago and it is still encountered as recently as five weeks ago. It represents this lack of awareness of the disease. But it's part of the bigger lack of awareness of liver disease because in part we talked about this disease being an inflammatory reaction of the liver. When most people hear the word inflammation, they relate to a personal experience maybe it was an inflamed tooth, maybe it was acne, and maybe it was a boil. It was something that hurt and it was red and it was swollen. When we talk about inflammation of the liver one has to know, the liver has no innervation for pain. It can be diseased, it can be inflamed, it can be scarred and really cause no major symptom that we associate with inflammation. Unless you're thinking about doing a liver panel and unless your mindset is that if there are abnormalities on the liver panel, you will pursue them diagnostically nothing helpful will be accomplished. Very often the person just looks good and they're saying, "I itch", so the focus is on the skin and liver disease is not considered. Most liver diseases are detected in asymptomatic patients who have abnormalities on liver panels. When we diagnose the earliest stages of diseases that's exactly the way a patient will present. In terms of awareness we need to be aware of diseases but the fundamental awareness we need to have is that adults with a variety of complaints should have a multiphase panel testing that includes liver tests. If there are abnormalities there, they need to be pursued. You can't look a patient in the eye and say well you look pretty good to me and maybe advise them to stop drinking alcohol which is all too commonly said even though their liver tests and their patterns would not be consistent with alcohol, nor with their consumption be consistent with alcohol. You can't ignore these. The call for awareness is to have people become astutely aware that liver tests abnormalities deserve an explanation. That a variety of symptoms can be the consequences of different organ system dysfunctions, such as itching being a consequence of liver disease and cholestasis. How do we start to develop the sense of awareness? I think the awareness really has to focus on the organ itself. We can do a better job than we're doing now.

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