Category Archives: Hepatology

Neutrophil function as a biomarker for Acute Liver Failure

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More data on impaired neutrophil function in acute liver failure (ALF) and subacute liver failure (SALF) is available (Hepatology 2013; 57: 1142-52).

This study examined 15 ALF patients and 10 SALF patients in a cross-sectional case-control cohort design who were admitted to the liver ICU at King’s College Hospital between 2008-2010.  The median age for the ALF group was 33 and for the SALF group it was 52.5.  Ultimately 10 survived without liver transplantation; the remainder either died or underwent liver transplantation.

Neutrophil function was assessed on admission and then serially every 3-4 days in several ways; these assays were compared with 6 septic controls and 11 healthy controls.  Phagocytic activity was measured with a “Phagotest,” which quantifies opsonization of labeled E. coli. Oxidative burst was measured with the “Burtest,” which determines the percentage of phagocytic cells that produce a reactive oxygen species.  Other tests examined neutrophil phenotype and cytokine measurements (TNF-α, IL-1β, IL-6, CXC8/IL-8, IL-10, and IL-17).

Key findings:

  • Impaired neutrophil phagocytic activity in both ALF and SALF cohort on admission predicted non survival without liver transplant (p=0.01).
  • Neutrophil expression of CD-16 was significantly reduced in ALF cohort on day 1 (p<0.001).

Take-home message:

This study demonstrates specific defects in neutrophil function in ALF/SALF that are similar to impaired bactericidal function in severe sepsis.  Neutrophil function assays, while not available at the bedside at this time, are important biomarkers in ALF/SALF for increased susceptibility for sepsis and death.

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Hepatocellular Carcinoma after the Fontan Procedure

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Given the fact that chronic liver disease and cirrhosis can develop in patients after the Fontan procedure, it comes as little surprise that cases of hepatocellular carcinoma (HCC) are being reported as well (NEJM 2013; 368: 1756-57).

This letter to editor describes four patients ages 24 to 42 who developed HCC following a classic Fontan or a variation.  Three of the four had very elevated alpha-fetoprotein levels; the lowest of the four patients was 106 ng/mL.  The letter notes that cirrhosis “may develop…approximately 11 to 15 years after a Fontan procedure; an incidence of cancer of 1.5 to 5.0% per year” is estimated after development of cirrhosis based on previous studies.

The letter also describes difficulties with regard to potential screening and treatment.

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Once Daily Tacrolimus for Liver Transplant Recipients

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A recent study shows that once daily tacrolimus can be effective in patients who have been stable following liver transplantation (LT) (Liver Transplantation 2013; 19: 529-33).

In this retrospective, single center study with 394 adult LT patients, the authors examined the results of conversion to once daily dosing of tacrolimus.  Patient demographics noted an mean age of 53 years & mean time post-transplant was 74 months.

Criteria for conversion:

  1. At least 6 months posttransplant
  2. No rejection in >3 months
  3. Tacrolimus bid was changed to the same total daily dose at once a day and then modified based on levels.

Results after a 24 month followup:

  • 358 of 394 were able to maintain once a day dosing. 6 patients had been converted to cyclosporine, 14 patients had stopped all calcineurin inhibitors, 16 patients had returned to BID dosing.
  • Acute rejection episode was noted in 7 patients
  • Mean serum tacrolimus trough decreased after conversion from 6.1 to 4.9 ng/mL

Take-home message:

Once daily tacrolimus appears to be a reasonable strategy for stable LT patients.  It is possible that once daily administration will improve adherence.

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More HCV options -phase 3 for Sofosbuvir

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The pace of research for HCV is incredible.  Two months ago phase 2 data for Sofosbuvir were reported and noted on this blog (More options for Hepatitis C | gutsandgrowth).  Now phase 3 data from multiple trials have emerged indicating the effectiveness of sofosbuvir for all HCV genotypes.

In the first study, NEJM 2013; 368: 1867-77, data from two trials (POSITRON and FUSION) of patients with HCV genotypes 2 and 3 are reported.  The POSITRON trial (63 sites, n=278 received treatment) was a blinded placebo-controlled study that evaluated 12 weeks of sofosbuvir/ribavirin compared with placebo in patients who discontinued interferon due to unacceptable adverse events or could not take interferon due to contraindications (most commonly psychiatric disorder or autoimmunity). Results: sustained virological response (SVR) in 78% of treatment group compared with 0% of placebo patients.  In addition, there was “complete concordance (100%) between rates of SVR at 12 weeks and at 24 weeks.”

The FUSION study (67 sites, n=201 received treatment) was a blinded, active-control study in patients who did not respond to a previous interferon-based regimen; one of two treatment regimens were administered: 12 weeks of sofosbuvir/ribavirin followed by placebo or 16 weeks of sofosbuvir/ribavirin. Results: 93% of genotype 2 patients had SVR and 61% of genotype 3 patients had SVR.  Among cirrhotic patients, 61% had SVR (94% of genotype 2, 21% of genotype 3); for those without cirrhosis, there was an 81% SVR (92% with genotype 2, 68% with genotype 3).  Thus, it is easy to conclude that genotype 3 patients with cirrhosis responded much less favorably.

Other important findings: rates of discontinuation among the treatment groups were similar to the placebo groups.  The most common adverse effect was anemia in the treatment groups.

In the second study, NEJM 2013; 368: 1878-87, an additional two phase 2 trials (NEUTRINO and FISSION) are reported from previously untreated chronic HCV patients.  The first trial (NEUTRINO) was an open-label study examining a 12-week regimen of sofosbuvir, peginterferon alfa-2a, and ribavirin in 327 HCV patients (98% genotypes 1 or 4).  Results: SVR noted in 90%. The second trial (FISSION) enrolled 499 patients with genotypes 2 and 3 who randomly received either peginterferon alfa-2a/ribavirin for 24 weeks or sofosbuvir/ribavirin for 12 weeks. Results: SVR noted to be 67% in both groups.  Genotype 2 patients again fared better than genotype 3 among the sofosbuvir/ribavirin group (97% versus 56%).  Some adverse events like fatigue, headache and nausea were common.  Overall, side effects were much lower in those not receiving peginterferon (see Table 3).

Take home message: From the editorial (pg 1931-32 in same issue): “a radical change in clinical practice is imminent…the low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drugs are strong selling points of a sofosbuvir-ribavirin regimen and will probably lower the threshold for HCV treatment for both patients and physicians.”

Hopefully, we will see pediatric studies soon.

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Microtargeting HCV

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“Where there is no vision, the people perish.” –King Solomon, Proverbs

A recent study (NEJM 2013; 368: 1685-94) sheds light on a new vision of potential therapies, using microRNAs designed to interfere with the pathogenesis intracellularly.  While this study used this technology to target the Hepatitis C virus (HCV), the same technology has already received FDA approval for a medication (mipomersen) used to treat familial hypercholesterolemia.

With familial hypercholesterolemia, antisense oligonucleotides were developed which inhibit the expression of apolipoprotein B-100 in the liver.  For HCV, miravirsen is a 15-nucleotide antisense oligonucleotide microRNA (miR-122) which binds two highly conserved sites in HCV RNA.  The liver-expressed miR-122 protects HCV from degradation. Thus, the antisense oligonucleotide miravirsen causes degradation of HCV.  All strains of HCV depend on miR-122. (This aspect is reiterated in an associated editorial: NEJM 2013; 368: 1741-43.)

This study enrolled 36 patients from 2010 to 2011 in a randomized, double-blind, placebo-controlled, sequential series, ascending multiple dose-ranging study (7 study sites).  All HCV patients had not received previous therapy and were genotype 1.  Patients received five weekly subcutaneous injections of miravirsen at 3 mg/kg, 5 mg/kg, 7 mg/kg or placebo injections.

Results: In the miravirsen groups, the mean maximum log reduction in HCV RNA level was related to dose: 1.2 in 3 mg/kg cohort, 2.9 in 5 mg/kg cohort, and 3.0 in 7 mg/kg cohort compared with a 0.4 reduction in the placebo cohort.  During 14 weeks of follow-up after completing treatment, HCV RNA was not detected in one patient in the 5 mg/kg group and in four patients in the 7 mg/kg group.

There were no dose-limiting toxic effects or treatment discontinuations because of adverse events.  However, cholesterol levels did decrease by ~25%. No viral resistance was identified.  In addition, during treatment with miravirsen, a sustained decrease in serum alanine aminotransferase was evident.

The authors note that the pharmacologic data from this study indicate that once-monthly regimen would be feasible.  Because miravirsen is not a substrate for P-450, it is not expected to have significant drug-drug interactions.  Further studies are underway.

Potential drawbacks of treatment: miR-122 is a tumor-suppressor gene for hepatocellular carcinoma (HCC).  Thus, treatment with miravirsen could increase the risk of HCC.  Also, in mice that lack miR-122, there is a high risk of fatty liver and fibrosis.

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Updated AASLD guidelines and Ascites

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The American Association for the Study of Liver Diseases (AASLD) updates all of its practice guidelines annually (AASLD: Practice Guidelines).  In adults with ascites due to cirrhosis, a recent publication highlights some of the more recent updates (Hepatology 2013; 57: 1651-53).

  • In adults, typically “cirrhosis cures hypertension.”  In addition, a prospective study has shown that propranolol shortens survival in patients with refractory ascites.  So, “consideration should be given to discontinuing beta-blockers or not initiating beta-blockers in those patients with refractory ascites.”
  • “Percutaneous endoscopic gastrostomy is advised against in patients with cirrhosis and ascites.”
  • “A meta-analysis of 17 trials involving 1225 patients..” demonstrates a reduction in mortality with albumin infusion after large-volume paracentesis.  Odds ratio of death with albumin infusion was 0.64.
  • There is an increasing prevalence of bacterial resistance due to widespread use of quinolines to prevent spontaneous bacterial peritonitis (SBP).  “It is prudent to limit prophylactic antibiotics to patients with well-defined criteria for SBP prophylaxis.”
  • A new biomarker (not available in U.S.) assists with the diagnosis of hepatorenal syndrome: urinary neutrophil gelatinase-associated lipocalin.
  • Vaptans are discussed in the update.  The largest trial with cirrhotic patients “demonstrated no clinical benefit in long-term management of ascites” and may increase mortality.

Finding the Right Specialist

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A recent clinical problem-solving case report highlights the fact that seeing the right specialist helps a great deal with pattern recognition (NEJM 2013; 368: 1345-51).  In this report, intriguingly titled “The Essential Element” the authors describe a 21-year-old who presented with refractory hemolytic anemia along with low albumin, low alkaline phosphatase, and elevated total & direct bilirubins.  Her course was somewhat protracted due to treatment of hemolytic anemia and lack of recognition of underlying hepatocellular disease.  After readmission three months later the diagnosis of Wilson’s disease was made and quickly she underwent orthotopic liver transplantation.

A couple of pointers from this article for me included the following:

  • Parenchymal injury from the oxidative effect of copper leads to the hepatocellular injury.  Release of copper also causes oxidative damage of erythroctye membranes.
  • The low alkaline phosphatase which is characteristic of Wilson’s is potentially due to the oxidative damage from free radicals or by competition at the active site of the alkaline phosphatase enzyme.
  • The combination of hemolysis with liver dysfunction should prompt consideration of Wilson’s.

Most hepatologists would quickly recognize the pattern presented in this case report.  Getting the patient to the right physician is the key.

Comprehensive review on Wilson’s:

Diagnosis and treatment of Wilson disease: An update – American …  AASLD Guidelines for Wilson disease.  This is an excellent resource for diagnosis and management.

Ultrasound Unreliable to Exclude Fatty Liver

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More information on the sensitivity of ultrasonography for detecting fatty liver is available in the setting of living-related liver transplantation (Transplantation 2013; 95: DOI: 10.1097/TP.0b013e31828d1588).

In this study the authors retrospectively examined the degree of steatosis from 492 living liver donors who had normal ultrasounds and normal aminotransferase levels. The median age of the donors was 30.1 year and the median BMI was 22.4 kg/meter-squared.

Background: According to the authors, if liver histology shows severe macrosteatosis (>60%), transplantation is canceled.  Furthermore, in cases of moderate macrosteatosis (30-59%), the risks/benefits need to be considered on an individual basis due to increased risk of mortality; Spitzer et al (reference below) demonstrated that macrovesicular steatosis >30% was an independent predictor of reduced 1-year graft survival.  In addition, a previous report has indicated that both macrosteatosis and microsteatosis had similar impacts on postoperative  liver function.

Results:

  • 3 (0.6%) had severe total steatosis, moderate or greater steatosis was diagnosed in 4 (0.8%) for macrosteatosis, in 26 (5.3%) for microsteatosis, and 56 (11.4%) for total steatosis.
  • There were two identified risk factors BMI >23 kg/meter-squared and triglycerides >88 mg/dL.  Individuals with both risk factors had a 28.6% prevalence of moderate or greater degree of total steatosis compared with 6.6% with no risk factors.  In these individuals, a liver biopsy may be worthwhile.

Why this study matters for the non-transplant physician:  This study provides additional data that ultrasonography is not adequate to exclude significant degrees of fatty liver.

Study limitations included the retrospective analysis which relied on medical record accuracy, degree of steatosis was not based on a single pathologist, ultrasonography was not based on not based on a single radiologist, both BMI and triglycerides may vary based on age, gender, ethnicity and other factors.

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Related references:

  • -Spitzer AL et al. Liver Transpl 2010; 16: 874-84.
  • -Liver Transpl 2013; 19: 437-49. Difficulty with precisely determining steatosis
  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -Gastroenterol 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound.

Hepatitis C Virus Sexual Transmission and Monogamy

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Numerous sources state that there is a low risk of transmitting Hepatitis C virus (HCV) among monogamous heterosexual couples.  More information on this subject has been published (Hepatology 2013; 57: 881-89).

In this study, 500 couples were studied; all were long-term heterosexual partners and all were HIV-negative.  The index partner was anti-HCV positive with a median age of 49 years and had a median of 15 years with their partner.  Condom use was infrequent among the study participants.

Key finding: HCV prevalence among partners was 4% (n=20) and ~2% (n=9) had concordant genotype/serotype.  The maximum prevalence of HCV transmission among these sexual partners was 1.2%.  Based on 8,377 person-years of follow-up, the maximum incidence rate of HCV transmission was reported as 0.07% per year or approximately one per 190,000 sexual contacts.

Some of the interesting aspects of the study included details of sexual activity and discussion of factors that may increase HCV transmission.  With regard to sexual activity, 30.4% of the couples reported prior anal intercourse and more than 90% reported oral sex (by both partners); however, both of these activities were reported as infrequent: typically 0 per month for anal intercourse and 3 contacts per month for oral sex.  With regard to HCV transmission, the authors did not identify any risk factors in the current study but did note that this may be influenced by viral titer, integrity of mucosal surfaces, and the presence of other infections.

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Liver toxicity -where to look online

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Increasingly physicians as well as families gather medical information online.  Physicians, like patients, benefit when they know that a website is highly regarded by experts in the field.  This month’s Hepatology (2013: 57: 873-74) provides an introduction to the website LiverTox (www.livertox.nih.gov) (Search Livertox Database).

This website provides comprehensive and “evidence-based information on drug, dietary supplement, and herbal-induced liver injury that is freely accessible to physicians, researchers, and the public.”  The website includes about 650 different medications, supplements, and herbals; more than 12,000 annotated references are available.  In addition, the website allows clinicians to submit a case report as well as allow submission to the FDA Adverse Event Reporting System (AERS).

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