Nonalcoholic Steatohepatitis Review

A concise and useful review of nonalcoholic steatohepatitis (NASH): AM Diehl, C Day. NEJM 2017; 377: 2063-72

A couple points:

  • About 25% of adults have fatty livers in the absence of excessive alcohol consumption
  • NASH is strongly associated with obesity/overweight which occur in  >80% of patients
  • NASH comorbidities in adults: 72% with dyslipidemia, 44% with type 2 diabetes mellitus
  • In a typical patient with NASH, liver fibrosis progresses “at a rate of approximately one stage per decade, suggesting that F2 fibrosis will progress to cirrhosis within 20 years.” However, there is considerable variability.
  • It is expected that NASH will be the leading reason for liver transplantation by 2020.
  • Cirrhosis related to NASH increases the risk of hepatocellular carcinoma with this occuring in 1-2% per year of patients with cirrhosis.
  • NASH is estimated to cost >$100 billion currently in annual direct medical costs
  • Staging of NASH and differentiation from isoloated steatosis identifies those at high risk for sequelae.
  • In Table 2, the authors list more than 10 pharmacologic agents in phase 2/3 studies

Current lifestyle treatment recommendations (for adults):

  • Lose 7% of body weight if overweight or obese
  • Limit consumption of fructose-enriched beverages
  • Limit consumption of alcohol (no more than 1 drink/day for women and 2 drinks/day for men)
  • Drink two or more cups of caffeinated coffee daily

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Panels A & B show typical histologic findings: ballooned hepatocytes (arrows), inflammatory infiltrates (arrowheads), and fibrosis Panel C shows the relative distribution of NASH, cirrhosis, and hepatocellular carcinoma in U.S. Adults.

Statin Use for Patients with Cirrhosis

There have been a number of studies suggesting a beneficial effect of statins for individuals chronic liver disease due to HBV infection, HCV infection, and nonalcoholic steatohepatitis. The potential reasons include lower portal hypertension due to increased nitric oxide availability, anti-inflammatory effects through reduction in some cytokines, and antifibrotic effects. In addition, statins may inhibit tumor initiation/hepatocellular carcinoma (HCC).

The background on these prior studies is detailed in a new population-based study (F-M Chang et al Hepatology 2017; 66: 896-907, editorial 697-9) of statins in patients with cirrhosis. In this nested case-control study from Taiwan, the authors examined patients (n=1350) with cirrhosis from 2000 to 2013.  The index cases of cirrhosis were identified among a representative, well-validated general population database of 1,000,000 people.

Key findings:

  • “Statin use decreased the risk of decompensation, mortality, and HCC in a dose-dependent manner.”
  • Risk of decompensation among chronic HBV statin users, HR 0.39
  • Risk of decompensation among chronic HCV statin users, HR 0.51
  • Risk of decompensation among alcohol-related cirrhosis patients taking statins, HR 0.69

My take: In adults with cirrhosis, particularly HBV-related and HCV-related, taking a statin was associated with a 50-60% lower likelihood of decompensation. A prospective study could confirm these findings.

Prague -Charles Bridge

Learned Fear of Gastrointestinal Sensations Plus Two

Briefly noted: The authors of a recent study (E Ceunen et al. Clin Gastroenterol Hepatol 2016; 14: 1552-58) set out to study whether it is likely that healthy adults could learn to fear “innocuous visceral sensations.”  Fifty-two healthy subjects received  2 types of esophageal balloon distentions –one that was perceptible and non-painful and one that was painful.  Not surprisingly, when the researchers paired these two interventions in the experimental group, the experimental group learned to fear the innocuous stimulation as well as the painful distention.  This study provides theoretical support for one mechanism that could trigger ongoing functional gastrointestinal symptoms and a potential rationale for therapies, like cognitive behavioral therapy, which attempt to extinguish these symptoms.

In a retrospective study (AM Moon et al. Clin Gastroenterol 2016; 14: 1629-37) with 6451 patients with cirrhosis (mean age 60.6 yrs), the authors note that use of antibiotics during upper gastrointestinal bleeding (which is currently recommended) is associated with reduced mortality by ~30% at 30 days.  Despite its benefit, this intervention is often overlooked.  In the current study, only 48.6% of admissions received timely antibiotics; however, during the course of the study, the rate of antibiotic use improved from 30.6% in 2005 to 58.1% in 2013.

A recent retrospective study (N Goossens et al. Clin Gastroenterol 2016; 14: 1619-28) with 492 subjects showed that histologic NASH (in 12% of cohort) was associated with increased risk of death in patients who underwent bariatric surgery compared to patients without NASH.  Overall, bariatric surgery reduced the risk of death during the study period with HR of 0.54; the median follow-up was 10.2 years, with surgery taking place 1997-2004.  However, in patients with NASH the HR 0.90 which indicated that there was not a significant reduction in the risk of death.

Bar Harbor, ME (low tide)

Bar Harbor, ME (low tide)

Bring Out the Big Guns: Treating Infections with Cirrhosis

A recent study (M Merli et al. Hepatology 2016; 1632-39) indicates that health-care associated infections (HCA) in the setting of cirrhosis respond more favorably to broad-spectrum antibiotics.  In this prospective study of 96 randomized patients, in-hospital mortality was improved in the broad-spectrum group (6%) compared to the standard group (25%).  There was a similar multidrug-resistnace rate (50% broad spectrum compared with 60% in standard group).

Table 1 lists the antibiotic selection.  In the broad spectrum treatment, this almost always included imipenem/cilastin (I/C); with spontaneous bacterial peritonitis (SBP), I/C was combined with vancomycin, and with pneumonia it was combined with both vancomycin and azithromycin.  In contrast, the standard group’s main medication was augmentin (with added azithromycin for pneumonia) or cefotaxime for SBP.

My take: Does this study show that infections in the setting of cirrhosis are becoming more difficult to treat? Probably. How much these findings can be extended to the pediatric population remains uncertain.

Somewhat related topic: Primary prophylaxis of Variceal Bleeding in Children –Summary of the Baveno VI Pediatric Satellite Symposium.  BL Shneider et al. Hepatology 2016; 63: 1368-80. Key point: “there are few pediatric data…therefore, no recommendations for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta-blockade in children was proposed.”

Silver Comet Trail

Silver Comet Trail

Hepatitis C Cure: Too Late for Many

Before the recent vast improvements in hepatitis C virus (HCV) treatment, there had been a number of studies predicting a huge increase in HCV-related mortality due to hepatocellular carcinoma (HCC) and cirrhosis.

Despite the optimism that have come with the new treatments, the most recent data (LA Beste, et al. Gastroenterol 2015; 149: 1471-82) continue to predict a huge and increasing burden of chronic liver disease due to HCV.

The authors used a national retrospective cohort of Veteran Affairs (VA) patients with cirrhosis (n=129,998) or HCC (n=21,326) from 2001-13.  They identified an increasing proportion of cirrhosis and HCC during that timeframe.

Key findings:

  • From 2001 to 2013, cirrhosis prevalence nearly doubled (664 –>1058 per 100,000 enrollees) driven by HCV and nonalcoholic fatty liver disease; deaths due to cirrhosis also increased from 83 to 126 per 100,000 patient years
  • From 2001 to 2013, HCC incidence increased 2.5-fold from 17 to 45 per 100,000 patient-years and HCC mortality tripled from 13 to 37 per 100,000 patient-years.  HCC incidence was driven overwhelmingly by HCV.
  • Based on current trends, cirrhosis prevalence will peak in 2021 according to the authors, though they acknowledge that patients from the VA may not be representative of the population at large and that the study has inherent weaknesses due to computerized data collection in this retrospective study.

My take: Despite dramatic improvements in HCV treatment, sadly, it is still going to get a lot worse with regard to disease burden & mortality from HCV before it will improve.

Briefly noted: F Negro. Gastroenterol 2015; 149: 1345-60.  “Extrahepatic morbidity and mortality of chronic hepatitis C”  This review article discusses diabetes, cardiovascular manifestations of HCV, fatigue, cognitive impairment, mixed cryoglobulinemia, and non-hodgkin lymphoma.

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Chattanooga Aquarium

Chattanooga Aquarium

Phase 3 Trial of Sebelipase Alfa for Lysosomal Acid Lipase Deficiency

A recent report (BK Burton et al. NEJM 2015; 373: 1010-20, editorial 1071-1) provides preliminary evidence of efficacy of Sebeliplase Alfa for lysosomal acid lipase deficiency.

In this multicenter, randomized, double-blind, placebo-controlled study of 66 patients, enzyme replacement therapy with Sebelipase alfa was examined (1 mg intravenously every other week).  After 20 weeks, all patients were treated by open-label. Of the 32 patients who had had liver biopsies, 10 (31%) were noted to have cirrhosis.


  • Alanine aminotransferase normalized in 11 (36%) of treated patients compared with 2 (7%) of controls
  • Improvement in lipid levels and reduction in hepatic fat content were evident in treated patients (P<0.001 for all comparisons, except P-0.04 for triglycerides

The editorial provides a schematic explaining how sebelipase alfa targets the hepatocyte (Figure 1).  The authors note that “longer-term follow-up in a larger number of patients will be required for confirmation.”

Related blog post:

Hepatitis C : New and Newer Treatments

A recent study (KR Reddy et al. Hepatology 2015; 62: 79-86) shows that the combination of ledipasvir/sofosbuvir is a safe, effective therapy for patients with genotype 1 Hepatitis C (HCV) and compensated cirrhosis.

The authors performed a post-hoc analysis of seven clinical trials in 513 treatment-naive and previously treated patients; 69% were previously treated. Key findings:

  • Overall, 493 (96%) achieved an SVR12; 98% of treatment-naive patients achieved an SVR12.
  • However, many patients in this analysis had received ribavirin.  In those treated without ribavirin (ledipasvir/sofosbuvir alone), the SVR12 was 90%.
  • Most common adverse effects included headache (23%), fatigue (16-19%), and asthenia (14-16%).

Bottomline: While ledipasvir/sofosbuvir was effective in this population, the 90% SVR12 is not as good as 96%.  This leads to the question of whether ribavirin is needed as well.

Related & briefly noted: SA Alqahtani et al. Hepatology 2015; 62: 25-30.  Ledipasvir/sofosbuvir treatment (8-24 weeks) resulted in SVR of 97% (with or without ribavirin) among the 1952 patients treated in the ION-1, ION-2, and ION-3 studies.

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From FDA (July 24th): FDA approves new treatment for chronic hepatitis C genotype 3 infections

The U.S. Food and Drug Administration today approved Daklinza (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection….

The safety and efficacy of Daklinza in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis.

From FDA (July 24th): FDA approves Technivie for treatment of chronic hepatitis C genotype 4

“The U.S. Food and Drug Administration today approved Technivie (ombitasvir, paritaprevir and ritonavir) for use in combination with ribavirin for the treatment of hepatitis C virus (HCV) genotype 4 infections in patients without scarring and poor liver function (cirrhosis).

Technivie in combination with ribavirin is the first drug that has demonstrated safety and efficacy to treat genotype 4 HCV infections without the need for co-administration of interferon, an FDA-approved drug also used to treat HCV infection…

The safety and efficacy of Technivie with ribavirin were evaluated in a clinical trial of 135 participants with chronic HCV genotype 4 infections without cirrhosis. Ninety-one participants received Technivie with ribavirin once daily for 12 weeks. Forty-four participants received Technivie once daily without ribavirin for 12 weeks. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 100 percent of the participants who received Technivie with ribavirin achieved a sustained virologic response. Of those who received Technivie without ribavirin, 91 percent achieved sustained virologic response.

Garden of the Gods, Colorado Springs

Garden of the Gods, Colorado Springs

Liver Update -January 2015

Briefly noted:

1. Gastroenterology 2014; 147: 1327-37 (editorial 1216-18).  “Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.” 66 patients received VSL#3 (9 x 10 to the 11th bacteria), 64 patients received placebo -both groups studied for 6 months. Treatment with lactulose and rifaximin were withdrawn a week prior to study entry. Key findings: ‘fewer hospitalizations for severe encephalopathy, better quality of life, and decreases in Child-Turcotte-Pugh class and Model for End-Stage Liver Disease.’  Hazard ratio for preventing hospitalization with VSL#3 was 0.52. However, the findings did not show that VSL#3 reached a statistically-significant reduction in recurrence rate for hepatic encephalopathy. No adverse events were noted.

2. NY Times: Gilead sued over cost of Sovaldi.

3. N Engl J Med 2014; 371:2375-2382.  Link to abstract: Interferon-free Antiviral Regimen for HCV after Liver Transplantation:  “Treatment with the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population.

4. “Transplantation Traffic –Geography as Destiny for Transplant Candidates” NEJM 2014; 271: 2450-52.  Describes ongoing geographic inequality in organ distribution and obstacles to improving allocation.

5. Liver Transpl 2015; 21: 57-62. Immediate Extubation After Pediatric Liver Transplantation –feasible in 67% according to this retrospective review.

Local Law Office  --Truth in Advertising?

Local Law Office –Truth in Advertising?

Pulmonary Complications Associated with Chronic Liver Disease

A useful review of “pulmonary complications in chronic liver disease” (Hepatology 2014; 59: 1627-37) has been published.

The main topics included hepatopulmonary syndrome (HPS) , portopulmonary hypertension (POPH), and hepatic hydrothorax (HH).

A few of the key points:

HPS is most common of these conditions and is identified in 5-30% of cirrhosis patients.  It is identified with abnormal oxygenation (screening with pulse ox <96%) due to intrapulmonary vascular dilatations. There is no established medical therapy.  It is reversible with liver transplantation.

The hallmark of POPH is the development of pulmonary arterial hypertension associated with portal hypertension.  It occurs in 5-10% of cirrhosis patients and often presents as dyspnea on exertion/fatigue.  There are numerous pharmacologic treatments that may be useful, include the following:

  • prostacyclin analogs like epoprostenol
  • endothelin receptor antagonists like boesentan
  • phosphodiesterase-5 inhibitors like sildenafil, vardenafil, and tadalafil

Severe POPH is a relative contraindication for liver transplantation.

HH is a transudative pleural effusion seen in 5-10% of cirrhosis patients. Initial management includes salt restriction and diuretics.  Transjugular intrahepatic portosystemic shunt and thoracentesis are second-line options.  Liver transplantation is curative.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.



Electronic Order Sets Can Improve Care

It is recognized that checklists can improve medical care as well as help you remember to pick up butter when you go shopping.  So, it is not surprising that a standardized electronic order set can improve patient care.  A recent prospective observational study has shown that implementation of an electronic order set improved the care of 123 patients with cirrhosis who presented with upper gastrointestinal hemorrhage (Clin Gastroenterol Hepatol 2013; 11: 1342-1348).

This study was conducted from 2011 to 2012.

Key findings:

  • Administration of antibiotics increased in patients in whom the order set was used: 100% compared with 89%. A previous Cochrane meta-analysis has noted a mortality risk reduction of nearly 20% in patients who received prophylactic antibiotics in this setting.
  • Order set usage was associated with quicker administration of antibiotics: 3h28min compared with 10h4min.
  • Time for octreotide administration was reduced in patients with the order set: 2h16min vs 6h21min.
  • Mortality was not reduced in this study by using an order set.  In fact, in those who used an order set there were 7 mortalities (out of 61) compared with only 2 mortalities (out of 62) who did not use order sets.

Order set use was at the discretion of the treating physician.  This could have led to selection bias.

Bottomline: Use of a standardized order set improved adherence and timeliness of recommended therapies.

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