Category Archives: Hepatology

Cholecardia

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An interesting study (MS Desai et al. Hepatology 2017; 65: 189-201) examines the effect of excess bile acids on the heart.  The abstract is listed below -I’ve highlighted what I find fascinating:

Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice.

CONCLUSIONS:

Decreased proliferator-activated receptor-γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart.

My take: There are a lot of reasons why having elevated bile acids is not a good thing. This study provides good evidence that these bile acids have specific cardiac toxicity.

Cozumel

Cozumel

HCV Treatment: Nearing 100% Effectiveness

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While access to HCV treatment remains the biggest obstacle, recent studies show that the rates of HCV eradication, even in the toughest cases, now approaches 100%.

  • E Lawitz et al. Gastroenterol 2016; 151: 893-901.
  • EJ Gane et al. Gastroenterol 2016; 151: 902-9.
  • Editorial: M Buti pgs 795-8.

Most prior studies examined the use of two direct-acting antivirals (DAAs) with or without ribavirin.  These DAAs targeted nonstructural (NS) proteins necessary for HCV replication: NS3 protease, NS5B polymerase, and NS5A protein.

These two new studies examined whether treatment with a DAA targeting all 3 NS proteins would be effective and possibly allow shorter treatments.  It is noted that currently only treatment-naive genotype 1 (w/o cirrhosis) patients have a regimen that is recommended for only 8 weeks; these patients also should have HCV-RNA<6,000,000 IU/mL.

Lawitz et al studied the combination of sofosbuvir-velpatasvir and GS-9857 (voxilaprevir) for 6-8 weeks (one treatment group received ribavirin); n=197. Among treatment-naive patients w/o cirrhosis, SVR12 was 100% after 8 weeks of treatment and 94% of treatment-naive patients with cirrhosis.  Among treatment-experienced patients treated for 12 weeks, 100% of all patients (w and w/o cirrhosis) achieved SVR12.

Gane et al studied the effectiveness of the combination of sofosbuvir-velpatasvir and GS-9857 in HCV genotypes 2, 3, 4, and 6 (as well as 1 with 1b); n=128. After 8 weeks of treatment, SVR12s were achieved in 93% of treatment-naive patients with cirrhosis.  After 12 weeks, treatment-experienced patients with and without cirrhosis had SVR12s of 97% and 100% respectively.

My take: This combination of therapies should allow shorter treatment regimens in treatment-naive patients and effective rescue therapy for previous DAA failures. Now that we can cure almost everyone with HCV, how do make therapies affordable and accessible?

Glacier Nat'l Park

Glacier Nat’l Park

Finding Residual Hepatitis C Virus in Liver Explants

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A recent report (M Gambato et al. Gastroenterol 2016; 151: 633-6) provides some insight into the importance of the presence of residual hepatitis C virus (HCV) RNA in the liver of patients undergoing liver transplantation.

The authors note that many patients with cirrhosis due to HCV do not complete a full course of antiviral therapy before liver transplantation as the waiting time is unpredictable.  The authors studied whether there was HCV RNA in the liver of 39 of these patients and tried to assess whether its presence was associated with relapse after liver transplantation.

Background:

  • Only 6 patients (15%) had completed treatment prior to liver transplantation.
  • Most patients (68%) had undetectable serum HCV RNA.
  • Treatment was most commonly sofusbuvir/ribavirin (n=30)

Key findings:

  • HCV RNA was detected in 26 of 39 liver explants (67%). Higher levels were detected in those who had received a shorter course of treatment at time of liver transplantation. Interestingly, HCV RNA was also detected in 2 (20%) of controls who had an SVR after completing an interferon-free treatment regimen.
  • 33 of 39 (85%) achieved a post-transplantation virologic response (pTVR) and 6 (15%) had recurrent HCV infection.  Thus, the persistence of HCV RNA in liver explant did not preclude pTVR.
  • Among the 26 patients with residual HCV RNA in the liver explant, a HCV RNA concentration was higher in the 4 patients that relapsed (23 vs 3 median copies/mcg total RNA).
  • Another unexpected finding was that among the 6 who relapsed, two had undetectable HCV RNA in liver explant –both patients carried mutations which could have rendered treatment less effective.  The authors note that HCV RNA could have been present at concentrations below detection or distributed unevenly (which could have affected testing).

The authors speculate that the presence of HCV RNA may have been sequestered in membranous webs which allowed the virus to avoid degradation/host defenses.

My take (borrowed from the authors): The presence of HCV RNA in the liver explant does not seem to be associated with treatment failure/virologic relapse after liver transplantation, except in case with high concentrations.

Maine’s oldest lighthouse: Portland Head Light

Portland Head Light

Portland Head Light

Is It Time To Start Testing HBsAg Levels in Hep B Patients?

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Two recent studies show that HBsAg levels may help determine therapeutic decisions:

  • WP Brower et al. Clin Gastroenterol Hepatol 2016; 14: 1481-89
  • Y-C Hsu et al. Clin Gastroenterol Hepatol 2016; 14: 1490-98.

The first study was a retrospective study of 292 HBeAg-negative patients with chronic hepatitis B virus (HBV) infection.  This cohort had normal ALT values and HBV DNA <20,000 IU/mL.  Patients were considered to be carriers of inactive HBV if their HBV DNA was <2000 IU/mL and serum levels of ALT remained normal.

Key findings with regard to likelihood of having inactive HBV at following year:

  • “odds were 97% for initial level of HBsAg <100 IU/mL”
  • “odds were 85% for patients with initial levels 100-1000 IU/mL and 76% for patients with initial levels >1000 IU/mL”

Also, “patients with HBV activity who had levels of HBV DNA <5000 IU/mL and decreases in HBsAg of 0.5 log IU/mL or more for 1 year had a high probability of becoming carriers of inactive HBV in the next year.” Figure 2 in an easy graphic form shows cumulative probabilities of becoming inactive or active HBV over the three-year period.

In the second study, Hsu et al performed a prospective study of 161 consecutive patients with undetectable HBV DNA following 3 or more years of entecavir.  After stopping therapy, patients were monitored for relapse.

Key findings;

  • 49.2% of patients had a clinical relapse (defined by elevation of both HBV DNA >2000 IU/mL and by elevated ALT >2-fold ULN)
  • 81.7% had virological relapse (HBV DNA >2000 IU/mL).
  • All patients with HBeAg-positivity had clinical relapse and were retreated.
  • For HBeAg negative patients at end of treatment, 39.2% had a clinical relapse & 77.4% had a virological relapse.
  • Serum HBsAg level predicted relapse among HBeAg-negative patients: 11 patients with HBsAg <10 IU/mL did not relapse. The lower the serum level of HBsAg at the end of treatment, the lower the rate of clinical relapse (see Figure 1).  Of those with HBsAg 100-1000, there was ~25% clinical relapse at 30 months f/u and more than 50% virological relapse.

My take: HBsAg level is becoming important in truly determining who has inactive HBV and reflects the likely natural history.  It is expected that using HBsAg levels will be increasingly used to determine management of HBeAg-negative HBV.

Related blog posts:

cligastroocthbv

Need Liver, Will Travel

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A recent commentary (G Cholankeril et al. Gastroenterol 2016; 151: 382-86) provides a succinct summary regarding the trends in liver transplantation multiple listing and its implications on notions of utility and justice.

Key points:

  • UNOS was established based on Congressional act in 1984: 42 U.S.C. § 274.  The principles of “justice” and “utility” were to be key in governing an equitable  allocation system.
  • Due to allocation inequities, however, some prospective liver transplant candidates seek multiple listings. From 2010 to 2015, 1082 of 70,080 (2%) liver transplant candidates on the waitlist had multiple listings. During that same time frame, 862 (multiply-listed) of 32,431(total transplants) (3%) underwent liver transplantation.
  • Candidates who migrated had “shorter waiting time before liver transplantation and higher probability of receiving an organ (multiple listings 80% versus primary listing 46%; P<.001)”
  • Multiple listing candidates had lower severity of illness and lower MELD score at time of liver transplantation (multiple listings 25 versus primary listing 28; P<.001)

Regional distribution:

  • 46% of the 862 multiply-listed patients who underwent liver transplantation received their organ in UNOS region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, Puerto Rico)
  • 67% of those 862 emigrated away from Regions 2, 5, and 9 -which have the longest waiting times. Figure 1 shows the 11 Regions.  Region 2 & 9 include New York, New Jersey, Delaware, West Virginia, Maryland, and Pennsylvania.  Region 9 includes California, Nevada, Arizona, New Mexico, and Utah.

My take: Under the current system, liver transplant candidates capable of travelling/multiple listing, are rewarded with earlier liver transplantation & higher likelihood of receiving a liver transplant.  Thus, until inequities in organ distribution are better addressed, patient’s may need to consider telling their transplant team: ‘Need Liver, Will Travel’

Related blog posts:

Public Art, New Orleans

Public Art, New Orleans

Obeticholic Acid in Primary Biliary Cholangitis

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While Primary Biliary Cholangitis (PBC) (previously called primary biliary cirrhosis) is seen mainly in adult hepatology practices, a new treatment may be emerging and this same medication is likely to be considered for several liver conditions.

Reference: F Nevens et al. NEJM 2016; 375: 631-43.

This 12 month, double-blind, placebo-controlled phase 3 “POISE” trial with 217 patients examined the use of obeticholic acid with or without ursodeoxycholic acid.  Surrogate markers of PBC were followed & the treatment groups improved compared to placebo.  However, adverse effects, particularly itching, were more common in the obeticholic acid groups; serious adverse effects were 11-16% in the treatment groups compared with 4% in the placebo group.

Results below:

PBC Rx

My take: It will be nice when important clinical endpoints can be assessed for this therapy like progression to cirrhosis.  For now, the cost of this treatment is ~$70,000 yearly.

Related blog post:

Breakthrough for Fatty Liver Disease? | gutsandgrowth

Optimistic Results for Hepatitis C plus Hepatology Update

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The August issue of Hepatology had several articles on Hepatitis C confirming the efficacy of newer agents:

  • LI Backus et al Hepatology 2016; 64: 405-14.  This “real-world” observational study from the VA Clinical registry with 4,365 genotype 1 treatment-naive patients who received ledipasvir/sofosbuvir showed SVR rates of 91.3% (w/o ribavirin) and 92% (w ribavirin).
  • P Kwo et al. Hepatology 2016; 64: 370-80 (OPTIMIST-1) This study showed that 12 weeks of simeprevir+sofusbuvir for 12 weeks was highly effective (97% SVR) and that 8 weeks of this therapy was inferior (83% SVR).  N=310 with genotype 1 (w/o cirrhosis).  No patients stopped therapy due to adverse effects.
  • E Lawitz et al. Hepatology 2016; 64: 360-69 (OPTIMIST-2) This study showed that simeprevir+sofusbuvir for 12 weeks was effective in genotype 1 patients (n=103) with cirrhosis.  For treatment-naive, the SVR was 88% and for treatment-experienced patients, the SVR was 79%.

Also in Hepatology:

  • S Heibani et al Hepatology 2016; 64: 549-55. This study looked at 1-week versus 2-week intervals for endoscopic ligation.  While 1-week ligation eradicated varices more quickly, neither approach was associated with differences in number of endoscopies, complications (including rebleeding) or other clinical outcomes.
From earlier study of "real-world" treatment of Genotype 1. Gastroenterol 2016; 150: 419-29.

From earlier study of “real-world” treatment of Genotype 1. Gastroenterol 2016; 150: 419-29. (Full text link)

 

Dubin-Johnson Syndrome

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From NEJM:

A 48-year-old woman scheduled to receive a laparoscopic cholecystectomy underwent a preoperative evaluation that disclosed conjugated hyperbilirubinemia…

A biopsy specimen revealed coarse, deep-brown, pigmented granules on periodic acid–Schiff staining (Panel B), primarily at the canalicular pole of the hepatocytes and especially in the pericentral zones, with otherwise well-preserved lobular architecture. Expression of the multidrug-resistance–associated protein 2 (MRP2) was absent on anti–MRP2 immunohistochemical analysis (Panel C; see also comparison with control specimen [inset]). A diagnosis of the Dubin–Johnson syndrome was confirmed. This syndrome is an autosomal recessive disorder that is caused by a mutation in MRP2 that results in deficient canalicular expression of MRP2 and impaired secretion of conjugated bilirubin into the bile. Such mutations cause an isolated increase in serum levels of conjugated bilirubin and the appearance of a black liver, without associated sequelae.

Dubin-Johnson

Do You Know When Hepatitis C Virus Transmission Peaked?

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According to a recent study (AC Spaulding, LS Miller. Lancet Infect Dis. 2016 Mar 30. doi: 10.1016/S1473-3099[16 …), peak transmission of hepatitis C virus (HCV) peaked about 1950, likely due to reuse of metal and glass syringes.

This study counters the idea that HCV transmission was “primarily due to injection drug use, unsafe tattooing, high-risk sex, and travel to high endemic areas during youth,” according to the researchers. Here’s the link: Apportioning blame in the North American Hepatitis C virus epidemic

My take: Will this take away some of the stigma of HCV infection? Probably not.  But, hopefully as the costs for treatment reduce, more individuals can be infection-free and avoid complications related to infections.

HCV Infections

Vedolizumab for Primary Sclerosing Cholangitis (with IBD)?

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“The monoclonal antibody vedolizumab may reduce biliary inflammation in patients with primary sclerosing cholangitis and comorbid inflammatory bowel disease, according to early, open-label study findings reported at the meeting sponsored by the European Association for the Study of the Liver”  –according to GIHepNews: Biliary inflammation reduced by IBD drug

“Vedolizumab given to 27 patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) resulted in a 50% reduction or normalization of serum alkaline phosphatase levels in 17 cases (63%).”

This was an open-label, proof-of-concept study involving 27 patients aged 25-30 years with PSC and comorbid IBD.

My take: This is interesting but needs a lot more study.

Atlanta Zoo 2016

Atlanta Zoo 2016