Category Archives: Hepatology

Microtargeting HCV

Posted on by

“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.

Related blog posts:

Updated AASLD guidelines and Ascites

Posted on by

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

Posted on by

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

Posted on by

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.

Related blog entries:

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

Posted on by

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.

Related blog posts:

Liver toxicity -where to look online

Posted on by

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).

Related blog entry:

More options for Hepatitis C

Posted on by

As noted in numerous blog entries (see below), there has been increasing availability of new and more effective treatments for Hepatitis C virus (HCV).  Two more drugs have promising results:

  • NEJM 2013; 368: 34-44
  • NEJM 2013; 368; 45-53

The first study provides encouragement with regard to sofosbuvir (previously known as GS-7977) which is a direct-acting nucleotide polymerase inhibitor targeting the NS5B polymerase.

In this open-label study, there were eight groups of patients.  Of 40 previously untreated patients (genotype 2 or 3), all patients received sofosbuvir (400 mg daily) for 12 weeks.  All 10 who received the study drug with ribavirin (& without interferon) and all 30 who received the study drug with ribavirin and peginterferon had a sustained virologic response (SVR) at 24 weeks.  Among patients with sofosbuvir monotherapy, 6 of 10 had a SVR.  Among HCV genotype 1 patients, 21 of 25 (84%) previously untreated patients had a SVR. The most common adverse effects were headache, fatigue, insomnia, rash and anemia.

The second study also was a phase 2a, open-label study for HCV genotype 1 non-cirrhotic patients using ABT-333 and ribavirin.  ABT-333 is a nonnucleoside NS5B polymerase inhibitor.  Results: 17 of 19 (89%) patients in group 1 (Rx with ABT-333, ribavrin, ABT-450, and ritonavir), 11 of 14 (79%) patients in group 2 (Rx with same drugs at lower doses of latter two drugs) had extended rapid virologic response.  SVR was achieved in 95% and 93% respectively.  Groups 1 and 2 were previously untreated.  Group 3 were patients who had either a null or partial response to previous treatment achieved a 47% SVR.  The most common adverse effects were abnormalities in liver function tests, headache, fatigue, insomnia, pruritus, nausea and rash.

Bottom-line:

These preliminary results suggest that Sofosbuvir is effective in all genotypes and may allow a short duration all-oral regimen.  ABT-333 similarly is effective in an all oral regimen in genotype 1 patients.

Related blog posts:

Can Hepatitis C really be cured?

Posted on by

While many have equated a sustained virologic response (SVR) as a cure for hepatitis C virus (HCV), there have been concerns about “occult” hepatitis C.  A new study indicates that in the vast majority of patients with an SVR, there is “no evidence of ongoing HCV replication…and no evidence that HCV replicates in PBMCs of chronically infected patients” (Hepatology 2013; 57: 483-91, editorial 438-40).

There has been no disagreement that an SVR is associated with improved liver histology, improved clinical symptoms, often a reversal of fibrosis, and lower risk of hepatocellular carcinoma.  However, the study and the accompanying editorial summarize the disparity in studies about the potential for occult HCV and how the virus has been identified in the peripheral blood mononuclear cells (PBMCs) and livers of patients who have had an SVR.

The study examined 67 chronic HCV carriers and examined the liver and other tissues of 2 spontaneously recovered chimpanzees.

Key findings:

  • The authors confirm that HCV RNA can be detected in PBMCs in chronic HCV carriers, but only as nonreplicating virus; therefore, it is probably not harmful to the host or to others.
  • Healthy controls had HCV passively adsorbed to PBMCs in vitro becoming indistinguishable from the HCV RNA in PBMCs of chronic HCV carriers
  • HCV RNA could not be detected in the PBMCs of 59 presumed recovered subjects using a highly sensitive nested PCR assay (measure down to 10 IU)
  • In total, this study and others support the likelihood of absolute HCV clearance in most patients with either spontaneous or treatment-induced recovery

Editorialist recommendation: “it seems appropriate to perform virology and biochemical screening annually…particularly if…there was histologic evidence of fibrosis or cirrhosis”

Related blog entries:

Gut microbiome and endogenous alcohol

Posted on by

At first glance, it sounds like an ambitious project -develop a gut microbiome that produces alcohol.  It could obviate the need for “Duff” beer (Duff Beer – Wikipedia, the free encyclopedia).  Yet, a recent article has found that an altered microbiome with increased endogenous alcohol already exists and it is associated with nonalcoholic steatohepatitis (NASH) (Hepatology 2013; 57: 601-609).

In this study, the authors examined three pediatric populations: a healthy control group (n=16), obese group (n=25), and NASH group (n=22).  All NASH patients had undergone liver biopsy and met Kleiner’s criteria; in contrast, the obese group had normal LFTs.

Key study findings:

1. The microbiome from the obese and NASH patients were similar but had some striking differences compared with the control group patients (pie chart –Figure 2):

  • Bacteroidetes (including Bacteroides): 28.65% in healthy controls, 50.28% in obese, and 49.11% in NASH
  • Firmicutes (including Blautia and Faecalibacterium): 66.78% in healthy controls, 42.62% in obese, and 42.39% in NASH
  • Proteobacteria (including Escherichia): 0.87% in healthy controls, 3.13% in obese, and 6.03% in NASH

2. Elevated serum ethanol concentrations only in NASH population: ~26 μM in both control and obese groups compared with ~35 μM in NASH patients.

Under normal conditions, endogenous alcohol is produced in the human body and the intestinal microflora are the major source.  This gut-produced alcohol is quickly metabolized by the liver.  Due to similar histology between NASH patients and patients with alcoholic liver disease, it has been hypothesized that NASH patients may have elevated blood alcohol.  This study adds further evidence to this hypothesis and provides a potential mechanism; namely, increased bacteria like Escherichia and Bacteroides can increase endogenously-produced alcohol.

Will efforts to revert the microbiome to normal have therapeutic effects on NASH?  This important question will need to be addressed given the growing problem of fatty liver disease.

Related blog posts:

Practice guidelines and 93 OLTx recommendations

Posted on by

While checklists have a role (Checklists for Crisis and Daily Care | gutsandgrowth), most will not be workable if each has 93 recommendations like the 2012 AASLD Adult Liver Transplant Practice Guidelines (Liver Transplantation 2013; 19: 3-26).

While the guidelines are comprehensive including topics like vascular thrombosis, immunosuppression, late rejection, bone health, kidney diseases, metabolic syndrome, reproductive health, and infectious disease, they are not easily organized.  Some recommendations include the following:

  1. “the frequency of monitoring with liver tests should be individualized by the transplant center (grade 1, level a)”
  2. “depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, ERCP, and ultrasound may be appropriate (grade 1, level a)”
  3. “frequent handwashing reduces the risk of infection…(grade 1, level a)”
  4. “shoes, socks, long-sleeve shirts and long pants should be worn for activities that will involve soil exposure..(grade 1, level a)”
  5. Patients “with PSC and inflammatory bowel disease…should undergo an annual screening colonoscopy ..(grade 1, level b)”
  6. “the ideal immunosuppression for pregnancy is tacrolimus monotherapy”

Thus, the recommendations are sometimes almost worthless like #1-3, sometimes difficult to implement like #4, and sometimes specific like #5-6.

Bottom-line:

While not useful as a practical checklist for routine care, this guideline offers useful information on a broad range of problems for transplant recipients.