Cirrhosis

Doctors are reporting the effectiveness of a screening method for patients with cirrhosis who are at risk for developing a common form of liver cancer known as hepatocellular carcinoma.¹

It's known as fine needle biopsy, a way to remove a very small piece of potentially cancerous tissue from the liver for examination under a microscope. Such examinations are performed to confirm a suspected diagnosis. In this case, the procedure is guided by an imaging method known as ultrasound, which allows doctors to easily see very small lesions on the liver. Then, they can very accurately remove small pieces of these lesions for study.

Hepatocellular carcinoma is the most common form of liver cancer in adults. It begins in the cells of the liver known as hepatocytes (heh-PAT-oh-sites). From there, the way it spreads can vary; some liver cancers of this type begin as a single tumor, which expands outwards. By contrast, another type spreads throughout the liver from the beginning and is not confined to a single tumor.² Hepatocellular carcinoma is the fifth most common malignancy in the world, and is believed to cause about a half million deaths around the world each year.³

In a more conventional liver biopsy used to screen for hepatocellular carcinoma, the physician examines a small piece of tissue taken from the liver. A special needle is used to remove this tissue. Biopsies are usually performed after tests suggest that liver disease may be present.⁴

Scrutinizing a Screening Method
The researchers who took part in this study in Italy say their research comes on the heels of guidelines issued by the European Association for the Study of the Liver (EASL) on the most effective ways to diagnose and treat patients with cirrhosis who are at greater risk for developing hepatocellular carcinoma. The recommendations urge regular ultrasound tests to check for possible signs of cancer in these patients, as well as immediate treatment interventions for those with confirmed liver tumors.

Similar guidelines have been published here in the U.S., recommending ultrasound exams every 6 months in high-risk patients, such as those with severe chronic hepatitis or cirrhosis.⁵

On the basis of those guidelines, several medical researchers in Italy wanted to evaluate the effectiveness of using ultrasound-guided fine needle biopsy to confirm hepatocellular carcinoma diagnoses in these patients.

In their large analysis, information was collected on 4375 patients. Then, investigators located information on the outcomes of more than 300 patients who had confirmed liver lesions. In 274 men and women in whom liver cancer couldn't be diagnosed except by performing a biopsy, the Italian investigators confirmed that definite liver cancer diagnoses had been made in each case. In those with non-malignant liver lesions, the diagnosis was confirmed after at least 1 year of follow-up exams using ultrasound tests during that time.

Findings: Ultrasound-Guided Biopsy is Reliable
Once they had compiled all the data, the investigators learned that ultrasound-guided, fine-needle biopsy confirmed the diagnosis of hepatocellular carcinoma in more than 89% of cases. "In a screening population, well over half of very small nodules arising in cirrhotic livers may prove to be hepatocellular carcinoma, and approximately 90% of these malignancies can be reliably identified with ultrasound-guided fine-needle biopsy," the research team concluded.

In an editorial accompanying this study,⁶a pair of German doctors praise the findings, noting that it provides information that's been sought in the field of liver cancer diagnosis for quite some time. They added that ultrasound-guided fine-needle biopsy "will probably define the gold standard of quality of this procedure."

But one limit to the study, stressed the German physicians from the University of Regensburg, is that it doesn't answer the question about in whom this type of liver biopsy would be valuable. Still, that "remains to some extent a bedside decision," they wrote.

Blocking liver rejection following a transplant procedure is not always an easy task for physicians. It typically requires a cocktail of immunosuppressive drugs aimed at preventing the body's immune system from attacking the new organ.¹From 1992 to 2001, nearly 30% of patients who underwent liver transplantation eventually rejected their organ, though that trend is an improvement from a high of about 50% 10 years ago.²

Now, doctors in Philadelphia claim a new combination of drugs might result in even fewer rejection episodes in liver transplant patients compared to current therapies.³

A Drug with a Positive History
The therapy they tested is a monoclonal antibody known as basiliximab (bas-il-IX-ih-mab), an immunosuppressive drug already used in kidney transplantation. The therapy works by fending off the body's white blood cells that launch an advance against the newly transplanted organ.⁴Basiliximab has traditionally been given by injection.

"… In general, a kidney transplant has a tendency to reject more aggressively than a liver transplant. Therefore, if this drug was proven to be successful in kidneys, I thought maybe we can achieve even better results in livers. And in fact, this was the case," explained Ignazio Marino, MD, head of the Division of Liver Transplantation and Hepato-biliary Surgery at Thomas Jefferson University Hospital in Philadelphia, and the study's chief investigator.

To test the hypothesis that basiliximab might also be beneficial for men and women undergoing liver transplant procedures, Marino and his fellow surgeons studied the results of 50 liver transplant operations they had performed from 2000 to 2002, using basiliximab as part of an anti-rejection treatment protocol that also included the traditional medication, tacrolimus (tuh-CRAW-lih-mus) and low doses of steroids. Their study was the first to use this regimen in liver transplantation. In the end, the study team noted a much lower incidence of liver rejection.

"We were able to prove that with the combination of this drug with the standard immunosuppression regimen using tacrolimus, rejections dropped from the historical rate of 40% to 12%, which is really a striking difference," said Marino, who is also a professor of Surgery at Thomas Jefferson University.

The results also suggest that this immunosuppression protocol may help improve a patient's odds of survival. Eighty-eight percent of the patients on which the study team focused were alive three years after transplantation, Marino and his colleagues noted. That compares to survival odds for the general liver transplant population of 78% after three years.⁵

The trial, he says, marks the first time that the basiliximab protocol has been tested for its efficacy and safety in liver transplant procedures. Marino notes that in the past 15 months of using this combination of drugs for liver transplants at his hospital, the chances of survival after 1 year has been 100%. Another advantage is that high doses of tacrolimus can be toxic to the nervous system and kidneys, and supplementing that with doses of basilixmab can reduce that risk." We think we have much less toxicity in the short term because we use less tacrolimus," he explains. Fewer steroids are also used in this regimen, which decreases the risk of toxicity even further. As a result, Marino says he and his colleagues expect fewer steroid-related complications, which can include high blood pressure, osteoporosis, and diabetes.

How Immunosuppression Works
Tacrolimus is a drug that suppresses the immune system by inhibiting an enzyme that's necessary for the production of T-cells, which make up part of the immune system. In the last decade, Marino says, researchers at the University of Pittsburgh developed a tacrolimus-based protocol that was considered an advance in the use of post-liver transplant immunosuppression.⁶ Its use greatly decreased the reliance on steroids, which can produce unwanted side effects. But tacrolimus produces its own side effects, such as an increased risk of infection in some cases, and anemia, among others, as well as its potential toxicity. Basiliximab inhibits the function of interleukin-2 in the body—a chemical messenger that calls certain immune system cells into action against a foreign invader.

"With the standard dose of 20 milligrams of basiliximab given at the time of surgery, and another 20 milligrams four days afterwards, you can decrease the dose of tacrolimus, and actually, you can even postpone the time that you start tacrolimus," Marino explained.

The approach is "revolutionary", he maintained, because rather than treating patients with aggressive immunosuppression immediately following liver transplant, this approach is much less aggressive, but still effective.

Targeting Hepatitis C
Another significant side effect of liver transplantation can be potentially avoided through the use of basiliximab: hepatitis C recurrence. "We suspect that the recurrence of HCV is lower, though we don't have enough data to confirm this," Marino explains. Typically, patients who undergo liver transplantation for hepatitis experience high rates of recurrence postoperatively.⁷ Perhaps basiliximab possesses some unique mechanism that blocks HCV replication, or the ability of the virus to make copies of itself, Marino says. That and other drugs that target interleukin-2 have hinted that they may be able to reduce the risk of recurrence.

"If this observation can be confirmed, it's important news because 60 percent of the patients we transplant are diagnosed with HCV," said Marino. "This would mean an immunosuppression that can delay the recurrence of HCV on top of having fewer episodes of rejection and toxicity than before."

While Marino would be interested in examining the mechanisms that underlie basiliximab's ability to keep HCV recurrence at bay, there is another clinical trial he has in mind first; one that would test the use of basiliximab alone, then adding tacrolimus after the transplant, without the use of steroids. "We are going to start this study soon with this aim," he said.

1. United Network for Organ Sharing (UNOS).
2. Scientific Registry of Transplant Recipients. University Renal Research and Education Association. University of Michigan. Trends in incidence of rejection at 1 year in liver transplant recipients.
3. Marino I, Doria C, Scott V et al. Efficacy and safety of basiliximab with a tacrolimus-based regimen in liver transplant recipients. Transplantation 2004 Sep 27;78(6):886-91.886-91.
4. Pascual J, Marcen R, Ortuno J. Anti-interleukin-2 receptor antibodies: basiliximab and daclizumab. Neprhol Dial Transplant 2001 Sep;16(9):1756-60.
5. Transplant Liver Registry. United Network for Organ Sharing (UNOS).
6. Abu-Elmagd K, Fung J, Todo S et al. The current status of hepatic transplantation at the University of Pittsburgh. Clin Transpl 1995;145-70.
7. Davis GL. Chronic hepatitis C and liver transplantation. Rev Gastroenterol Disord 2004 Winter;4(1):7-17.

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.

Persistent ascites and low serum sodium identify patients at high risk of early death

Persistent ascites and low serum sodium identify patients with cirrhosis as having a high mortality risk despite low MELD scores, states a report published in the most recent issue of Hepatology.

Despite the sickest patients taking priority for liver transplants, pre-transplant death remains common, and many early deaths occur despite initially low Model for End-stage Liver Disease (MELD) scores.

Researchers in Virginia, America studied 507 cirrhotic United States' veterans who had been referred for consideration of liver transplantation between 1997 and 2003, in order to identify additional predictors of early mortality.

Most of the patients were male (98%) and in 88% of the cases cirrhosis was found to be caused by hepatitis C and/or alcohol.

The researchers analyzed data for a total of 296 patients referred prior to February 27, 2002 (training group).

Any findings were then validated by further analysis of 211 patients referred subsequently (validation group).

61 patients from the training group, (21%), died within 180 days without transplantation. Their median initial MELD score was 21.

MELD score, persistent ascites, and low serum sodium (<135 meq/L) were found to be independent predictors of early mortality.

Persistent ascites and low serum sodium identify patients with cirrhosis as having a high mortality risk despite low MELD scores

Hepatology

Where patients had a MELD score of less than 21, the researchers found that only low serum sodium and persistent ascites were independent predictors of mortality.

For patients with MELD scores above 21, only MELD was independently predictive.

Analysis of the validation group then confirmed the prognostic significance of persistent ascites and low serum sodium for low MELD score patients.

Risk varied continuously with worsening hyponatremia.

The researchers found that modifying MELD, by including points for persistent ascites and low serum sodium, improved prediction of early pre-transplant mortality in low MELD score patients.

Dr Heuman concluded, "Persistent ascites and low serum sodium identify patients with cirrhosis as having a high mortality risk despite low MELD scores".

He commented that "Further prospective studies are required into ascites, hyponatremia, and other findings indicative of hemodynamic decompensation that may be prognostic indicators in patients awaiting liver transplantation".

Hepatology; 2004:40:802-810
24 September 2004

Bacterial infections in cirrhosis

G Garcia-Tsao

Hospitalized patients with cirrhosis are at increased risk of developing bacterial infections, the most common being spontaneous bacterial peritonitis (SBP) and urinary tract infections. Independent predictors of the development of bacterial infections in hospitalized cirrhotic patients are poor liver synthetic function and admission for gastrointestinal hemorrhage. Short term (seven-day) prophylaxis with norfloxacin reduces the rate of infections and improves survival and should therefore be administered to all patients with cirrhosis and variceal hemorrhage. Cirrhotic patients who develop abdominal pain, tenderness, fever, renal failure or hepatic encephalopathy should undergo diagnostic paracentesis, and those who meet the criterion for SBP (eg, an ascites neutrophil count greater than 250/mm³) should receive antibiotics, preferably a third-generation cephalosporin. In addition to antibiotic therapy, albumin infusions have been shown to reduce the risk of renal failure and mortality in patients with SBP, particularly in those with renal dysfunction and hyperbilirubinemia at the time of diagnosis. Patients who recover from an episode of SBP should be given long term prophylaxis with norfloxacin and should be assessed for liver transplantation.

Key Words: Cirrhosis; Gastrointestinal hemorrhage; Infections;

Spontaneous bacterial peritonitis

http://www.pulsus.com/Gastro/18_06/tsao_ed.htm

Management of spontaneous bacterial peritonitis (SBP)

SBP is an infection of ascites that occurs in the absence of a contiguous source of infection (e.g., intestinal perforation, intraabdominal abscess). The prevalence of SBP in hospitalized cirrhotic patients ranges between 10-30%. The diagnosis should be suspected in any patient with ascites who develops local or systemic signs of infection, encephalopathy or renal dysfunction and the diagnosis confirmed with the presence of an ascites polymorphonuclear (PMN) count >250/mm³ [7]. The preferred therapy for SBP is the use of intravenous antibiotics, mainly cefotaxime or another third generation cephalosporin (ceftriaxone, ceftazidime) or the combination of a b-lactam/b-lactamase such as amoxicillin/clavulanic acid [7]. The intravenous preparation of amoxicillin/clavulanate is not available in the United States and therefore the combination of ampicillin/sulbactam could be used instead. In patients with community-acquired SBP, no encephalopathy and a normal renal function, orally administered quinolones with a high bioavailability (ofloxacin, levofloxacin) are an acceptable alternative [20], provided that the local prevalence of quinolone-resistant organisms is low. In patients with renal dysfunction, either at baseline or during treatment, plasma expansion with albumin should be used as an adjunct to therapy [21]. Treatment should be administered for a minimum of 5 days, preferably for 8 days. A control paracentesis performed 48 hours after starting therapy is generally necessary to assess the response to therapy and the need to modify antibiotic therapy and/or to initiate investigations to rule out secondary peritonitis. In the presence of an obvious clinical improvement, control paracentesis may not be necessary.

http://www.hcvadvocate.org/hcsp/articles/Khalid_Garcia-Tsao-1.html

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	Improving Liver Cancer Detection in Cirrhosis is Study Aim
	New Liver Rejection Treatment Approach Demonstrates Its Merit, Doctors Say
	Persistent ascites and low serum sodium identify patients at high risk of early death
	Bacterial infections in cirrhosis