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CIRRHOSIS
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Intercept Pharmaceuticals Announces Publication of Study Demonstrating Its Lead Compound Can Reverse Liver Fibrosis
JAMA
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| A high proportion of patients with compensated liver disease can be accurately diagnosed with cirrhosis using Doppler ultrasound signs, including the new hepatic vein spectrum, reports an article in the European Journal of Gastroenterology and Hepatology. | |
| Christophe Aube and colleagues have determined whether ultrasound, and particularly, new Doppler signs, increase the diagnostic accuracy of the most accurate, currently available markers for the diagnosis of cirrhosis or severe fibrosis. They studied a total of 32 clinical (n = 4), biochemical (n = 11) and Doppler ultrasound (n = 17) variables that were recorded in 106 patients with compensated chronic liver disease. In order to evaluate diagnostic accuracy, discriminant analysis was used, first globally, and then using all variables by variable analysis. For diagnosis of cirrhosis using Doppler ultrasound, diagnostic accuracy was 92% globally, and 89% with 3 variables (spleen length, hepatic vein spectrum and maximum portal vein velocity). Based upon clinical signs, diagnostic accuracy was 86% globally, and 85% with one variable (firm liver). When basing findings upon biochemical parameters these values fell to 80% globally, and 81% with two variables (hyaluronate and platelet count). Based upon all parameters, diagnostic accuracy was 91% globally, and 91% with four variables (firm liver, hyaluronate, platelet and hepatic vein spectrum). On an intention to diagnose basis, Doppler ultrasound provided a lower independent contribution due to missing data. In the diagnosis of severe fibrosis, diagnostic accuracy was 83% globally, and 77% with one variable. The researchers, who have published their study in the August issue of the journal, conclude that cirrhosis can be correctly diagnosed in approximately 90% of patients with compensated chronic liver disease using a few Doppler ultrasound signs including a new sign, the hepatic vein spectrum. They add that Doppler ultrasound could be used for the first line diagnosis and biochemical markers, such as hyaluronate, in patients with missing Doppler ultrasound data.
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Eur J Gastroenterol Hepatol 2004: 16
(8): 743 - 751 19 July 2004 |
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by John C. Martin |
Article
Date: 07-07-04 |
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One common side effect of liver cirrhosis is fatigue.
A Common Symptom
It's a symptom that's "very common", striking "65 to 70 percent" of
cirrhotic patients, explained Douglas Dieterich, M.D., vice chair and
chief medical officer in the department of Medicine at Mount Sinai
Medical Center in New York. Dieterich and a team of researchers
released a study on the subject at Digestive Disease Week 2004, a
gastroenterology conference held in New Orleans in May.2
Fatigue in cirrhosis is a phenomenon that has had little focus in the medical literature, Dieterich told Priority Healthcare, in a telephone interview. In fact, this was the first study to examine its effects in people with cirrhosis, he said.
In these patients, liver cells are damaged and can't repair themselves. As the liver cells die, scar tissue forms, and as it builds up, blood flow through the liver gets blocked. In turn, blood doesn't get filtered properly, and poisons and wastes can build up in the body. This is the condition that becomes dangerous to the patient.3
Fatigue can crop up not only from the cirrhosis (or the hepatitis itself), but also from the medications that are typically prescribed, such as pegylated interferons (Pegasys, PEG-Intron) and the anti-viral medication, ribavirin.
Managing Fatigue: Few Options
Sometimes, if side effects are too overwhelming for patients on these
medications, such as when anemia occurs, physicians may reduce their
dosage.4 Anemia is a condition in which there aren't enough
healthy red blood cells to carry oxygen to the body's tissues, which
manifests itself as fatigue.5 But doctors don’t have
therapeutic options to treat cirrhosis-related fatigue. "Well, nobody
else is using anything for it, frankly," Dieterich said. "They're just
telling the patients to rest more."
In some cases, experts have suggested that fatigue in patients with hepatitis C (HCV) may be related to the severity of their depression, rather than the hepatitis itself, and recommend prescribing anti-depressant medications in these cases.6
But fatigue can still be a side effect in patients in which there is no available treatment, and medical experts are just beginning to understand its impact.7,8
Medications Under Scrutiny
One medication is getting some attention, however. In some
cases, doctors prescribe recombinant erythropoietin, a drug that helps
the body boost its production of red blood cells, and thus, alleviate
fatigue. Erythropoietin is marketed under such brand names as Procrit
(Ortho Biotech) and Epogen (Amgen).
In a previous clinical trial published in May, Dieterich teamed up with doctors at Harvard University to test the effects of epoietin alfa—a manmade version of erythropoietin—as a treatment for anemia in cirrhotic patients with fatigue.9 In 185 patients, the investigators found that the medication significantly improved hemoglobin levels, and helped more patients maintain their dosage of ribavirin.
Measuring the Impact of
Fatigue
In the new study, Dieterich and his associates recruited 100 patients
with cirrhosis being treated at a liver transplant clinic. Each
patient underwent a comprehensive examination for liver disease
severity, anemia, and the presence of cardiopulmonary disease—a common
contributing factor to fatigue in such patients.
The doctors then measured levels of fatigue using a special Fatigue Severity Scale and asking patients to walk as far as they could for 6 minutes—a standard exercise test.
The researchers assessed each patient's related quality of life using a special questionnaire. The additional influence of anemia was then tested, as well.
What the Investigators Found
"Fatigue was a common complaint," the study authors wrote. Patients
scored relatively high on fatigue measurements, and the average
distance walked in 6 minutes was 266 meters (291 yards). Those who had
higher levels of severity were less likely to travel farther in the
walking test, and "correlated with poor quality of life."
Normal hemoglobin levels in the average adult range
from 12 to 18 grams per deciliter (g/dL).(9) In this study, average
hemoglobin levels stood at 12.4 g/dL, with the lowest level at 7.3 g/dL,
the investigators found. Thirty-four of the patients were considered
anemic.
After taking each patient's age into account—older people generally
have lower hemoglobin levels—the researchers discovered that ascites
(a condition characterized by high abdominal fluid levels), higher
weight, severity of liver disease, difficulty absorbing oxygen, and
anemia tended to negatively affect a patient's ability to travel
farther in the walking test.
"Severe fatigue … is common in cirrhotic patients, and high fatigue
scores are associated with poor quality of life," the study
researchers concluded.
They added that if certain medications prescribed for anemia are also
effective for patients with cirrhosis, the findings will be
significant for patients. "Demonstration that human recombinant
erythropoietin therapy improves the anemia of cirrhotic patients will
have important therapeutic implications," the research team wrote.
1. American Gastroenterological Association.
2. Anemia is a major determinant of fatigue in patients with
cirrhosis. Digestive Disease Week 2004. 2004 May 15-20. New Orleans,
LA.
3. American Academy of Family Physicians.
4. Fried MW. Side effects of therapy of hepatitis C and their
management. Hepatology 2002 Nov;36(5 Suppl 1):S2370-44.
5. Mayo Foundation for Medical Education and Research.
6. Dwight MM et al. Depression, fatigue, and functional disability in
patients with chronic hepatitis C. J Psychosom Res. 2000
Nov;49(5):311-7.
7. van Mens-Verhulst J, van Dijkum C et al. Dealing with fatigue: The
importance of health-related action pattierns. Patient Educ Couns
1999 Jan;36(1):65-74.
8. Glacken M, Coates V et al. The experience of fatigue for people
living with hepatitis C. J Clin Nurs 2003 Mar;12(2):244-52.
9. Afdhal NH, Dieterich DT, Pockros PJ et al. Epoetin alfa maintains
ribavirin dose in HCV-infected patients: A prospective, double-blind,
randomized controlled study. Gastroenterology 2004
May;126(5):1302-11.
John Martin is a long-time health journalist and an
editor for Priority Healthcare. His credits include coverage of health
news for the website of Fox Television's The Health Network, and
articles for the New York Post and other consumer and trade
publications.
http://www.hepatitisneighborhood.com/content/in_the_news/archive_1947.aspx
Introduction A 47 year-old business executive came to me with fatigue and swelling in her legs. She said that for the past 6 months she had felt more tired than usual, but attributed it to putting in longer hours at work. She became more concerned when she developed swelling in her legs and her doctor told her she had an enlarged spleen. Her doctor thought she may have a liver problem and she wanted to know what she should do. Cirrhosis is irreversible end-stage liver disease,
and is the eleventh leading cause of death in the United States. In a
cirrhotic liver, the normal liver cells transform into nonfunctioning
cells, and the architecture of the liver is altered, leaving it bumpy
and scarred. My patients are often surprised to learn that excessive
alcohol consumption is not the only cause of cirrhosis. Other potential
causes of cirrhosis include viral hepatitis,
some metabolic disorders (such as
hemochromatosis) and
autoimmune diseases. Sometimes a cause
of cirrhosis is not even found. Diagnosing Cirrhosis There are different degrees of cirrhosis ranging from mild to severe, and they can be graded using the Child-Turcotte-Pugh scoring system. You can determine the degree of cirrhosis by blood tests that measure proteins and bilirubin, which are manufactured and processed by the liver. There are a number of diagnostic approaches to this disease, including liver biopsy, careful attention to patient history and symptoms, blood tests, and x-rays. Liver Biopsy Patient History and Symptoms
However, there are clues doctors can look for as they approach a diagnosis. Heavy alcoholic drinking and chronic hepatitis are both states that can result in liver damage, and so may support a diagnosis of cirrhosis. Patients may complain of fluid in their legs (edema) or swelling (distension) of the abdomen. Some patients may have disabling symptoms such as fatigue, fluid retention, or confusion. But again, they may have no symptoms at all. Sometimes the only findings suggestive of cirrhosis are in the blood work. Blood work X-rays These findings on ultrasound or CT scan, along with
the information provided by laboratory blood work, the history, and the
physical exam can be used to make the diagnosis of cirrhosis. In unclear
cases, a liver biopsy can be performed to confirm clinical suspicion.
Cirrhosis Complications Imagine that the normal liver is a brand new sponge that grows soft and pliable after it is wet with water. Now imagine an old used sponge that is hard, and crumbles when squeezed. Water easily flows through the new sponge, but has a harder time passing through the old sponge. A cirrhotic liver is like an old sponge. Elevated pressure in the liver prevents blood from passing through it freely and normally. Complications from cirrhosis result from the high pressures in the liver and abnormal flow of blood. Bleeding Fluid retention Encephalopathy Individuals with cirrhosis may experience none or all
of these symptoms, but when they develop any one of these complications
then they are said to have decompensated
cirrhosis. Treatment of Complications Patients often say to me, “I’ve heard that liver cells can regenerate. If the liver can regenerate then why can’t it recover from cirrhosis?” The normal liver can regenerate, but a liver with cirrhosis does not contain normal liver cells. Once cirrhosis has occurred therapy is
supportive, meaning the damage to the
liver has been done and only the complications resulting from the damage
can be treated. This includes diet and fluid pills (diuretics)
for patients with fluid retention. Individuals with bleeding may be
treated with oral medication or endoscopy
(a procedure where a long tube with a camera is inserted through mouth
and into the stomach; bleeding areas can be stopped by burning them or
by injecting a substance that causes the blood vessels to close). The
encephalopathy associated with cirrhosis can be treated with a
lactulose (a liquid medication that
causes a diarrhea which lowers the level of harmful toxins in the body).
In severe cases patients with cirrhosis may require liver
transplantation. My patient with the fatigue and swelling in her legs did in fact have cirrhosis. Her records showed she had a low platelet count and an ultrasound showed an enlarged spleen and fluid in her abdomen (ascites). On further evaluation her blood work demonstrated that she might have autoimmune hepatitis, a disease in which the body attacks the liver and causes scarring. I performed a liver biopsy to confirm the diagnosis of autoimmune hepatitis so she could start on the appropriate treatment. She was very surprised that she had cirrhosis. She
thought cirrhosis was only from heavy alcohol drinking and she rarely
drank. Also, she could not understand how she could feel so well with
cirrhosis. I explained that alcohol abuse is not the only cause of
cirrhosis and there are many other causes. We also discussed the wide
spectrum of symptoms that go along with cirrhosis from having no
symptoms at all to feeling very ill. Commonly Asked Questions Even if I have cirrhosis, doesn’t
the liver grow back and replace the damaged portion? I’ve been diagnosed with cirrhosis
and my doctor did not even do a liver biopsy. Is this possible?
If, however, there is doubt about the cause of the cirrhosis or the diagnosis itself, a liver biopsy is very useful. Is there any special diet I should
be on? Conclusion The liver is an important organ involved in many critical functions. It is fairly forgiving and can repair itself after injury, but will succumb to repeated insult and negligence. Therefore, it is important to stop any ongoing injury to the liver before this critical organ sustains damage that is irreparable. The take home message is: Take care of yourself and love your liver! Prevention of Hepatocellular Carcinoma6 July 2004 | Volume 141 Issue 1 | Pages 77-78
IN RESPONSE: We agree that the information Dr. Stark describes should be fully explained to patients and health care providers. However, we believe that current antiviral therapies, because of their relatively low efficacy and effectiveness, are unlikely to cause major changes in the epidemic of HCV-related hepatocellular carcinoma in the near future. Persons likely to have a demonstrable therapy-related reduction
in risk for hepatocellular carcinoma are those with advanced
fibrosis and cirrhosis. The validity and generalizability of
the randomized, controlled trial cited by Dr. Stark
(1) are questionable. That study was conducted in Japan,
patients were treated with a high dosage of interferon- For patients without advanced fibrosis or cirrhosis, the benefit of antiviral therapy in reducing risk for hepatocellular carcinoma is far less clear. Approximately 20% and 1% to 2% of all HCV-infected persons develop cirrhosis or hepatocellular carcinoma, respectively, and there are reliable predictors of those who will develop these complications (3). On the other hand, 20% to 50% of those treated achieve sustained viral response. Therefore, it is not at all clear whether those destined to develop cirrhosis and hepatocellular carcinoma will reap the benefits of reducing the risk for these disorders. Last, and perhaps most important, there is a discrepancy between the efficacy of antiviral therapy in randomized, controlled trials, mediocre as it is, and the disappointing effectiveness obtained in real life, even in dedicated management settings. Comorbid psychiatric disorders, including alcohol and drug use (4); side effects of antiviral therapy (particularly in patients with cirrhosis); and preponderance of "unfavorable" genotype I lead to low participation, low adherence, and eventually low response rates (2, 5). In summary, HCV infection is probably responsible for at least a proportion of the observed increase in hepatocellular carcinoma in the United States. While current antiviral therapy may benefit some patients, especially those with advanced disease, uncertainties about predictors of the clinical course of HCV infection coupled with relatively low efficacy and especially effectiveness of therapy prohibit a sweeping recommendation.
1. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;346:1051-5. [PMID: 7564784].[Medline] 2. El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology. 2002;36:74-83. [PMID: 12407579].[Medline] 3. Seeff LB. Natural history of hepatitis C. Am J Med. 1999;107:10S-15S. [PMID: 10653449].[Medline] 4. El-Serag HB, Kunik M, Richardson P, Rabeneck L. Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology. 2002;123:476-82. [PMID: 12145801].[Medline] 5. Falck-Ytter Y, Kale H, Mullen KD,
Sarbah SA, Sorescu L, McCullough AJ. Surprisingly small
effect of antiviral treatment in patients with hepatitis C. Ann Intern Med.
2002;136:288-92. [PMID: 11848726]. About Letters
The Editors welcome submissions for possible publication
in the Letters section. Authors of letters should: This article has been cited by other articles:
he Editors Related articles in Annals:
Two recent studies examined the natural history
of liver cirrhosis in individuals with viral hepatitis. In the May issue of
Gut, L. Benvegnu and colleagues investigated the progression and
outcome of initially compensated cirrhosis in a cohort of 312 Italian
patients with hepatitis B (43 patients), C (254 patients), or both (15
patients), followed for an average of about eight years. Tests were
performed every six months to assess liver disease progression and identify
major complications. During the follow-up period, 102 patients (about 33%)
developed at least one complication. The most common were hepatocellular
carcinoma (HCC, a type of liver cancer; about 21%), ascites (about 20%),
gastrointestinal bleeding (about 5%), and encephalopathy (about 2%). About
20% experienced liver disease progression as evidenced by an increased
Child-Pugh cirrhosis score. About 19% died from liver disease during
follow-up, most (70%) due to HCC. The authors concluded that HCC was “the
most frequent and life-threatening complication, particularly in HCV
positive cases.”
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(6 MU 3 times weekly), and the reported risk reduction can mostly
be attributed to the unusually low number of hepatocellular
carcinoma cases in the control group. The retrospective studies
cited by Dr. Stark are prone to inflated estimates of benefit
because of selection bias favoring better outcomes among treated
patients 