FITCH Study of Bezafibrate for Pruritus Due to Cholestatic Liver Disease

In the Fibrates for Itch (FITCH) study, (E de Vries, R Bolier e al. Gastroenterol 2021; 160: 734-743. Full text pdf: Fibrates for Itch (FITCH) in Fibrosing Cholangiopathies:A Double-Blind, Randomized, Placebo-Controlled Trial), the authors study bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist.

Key findings:

  • 70 patients completed the trial (44 PSC, 24 PBC, 2 SSC) (SSC =secondary sclerosing cholangitis). Treated patients received bezafibrate 400 mg once a day for 21 days.
  • For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to >/=50% reduction of severe or moderate pruritus (P ¼ .003).
  • Bezafibrate also reduced serum alkaline phosphatase (35%, P ¼ .03 vs placebo) correlating with improved pruritus (VAS, P ¼ .01) suggesting reduced biliary damage.
  • Serum bile acids and autotaxin activity remained unchanged.

My take: While the majority of patients did not reach the primary end point, bezafibrate merits further investigation and may be a useful agent for pruritus in the setting of cholestatic liver disease. From the associated editorial (pg 649, JK Dyson et al. Bezafibrate for the Treatment of Cholestatic Pruritus: Time for a Change in Management?): “FITCH is an important study and provides novel and important data. It suggests that bezafibrate can be part of the answer to cholestatic pruritus.”

From Editorial:

Current treatment ladder for pruritus and the potential positioning of bezafibrate in the future.

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Yesterday’s post alluded to alcoholic liver disease. More on that topic from NPR:

Link: Sharp, ‘Off The Charts’ Rise In Alcoholic Liver Disease Among Young Women

Cases of alcoholic liver disease — which includes milder fatty liver and the permanent scarring of cirrhosis, as well as alcoholic hepatitis — are up 30% over the last year at the University of Michigan’s health system, says Dr. Jessica Mellinger, a liver specialist there….

In the U.S., more than 44,000 people died of alcoholic liver disease in 2019. And although liver diseases still affect more men, younger women are driving the increase in deaths, a trend that began several years ago and is now supercharged by the pandemic

Here’s A Bad Idea-Alcohol Consumption on the Day of Liver Transplantation

Yes –there is a retrospective study describing outcomes for patients who consume alchohol on the day of liver transplantation: J Ursic-Bedoya et al. Liver Transplantation 2021; 27: 34-42. Alcohol Consumption the Day of Liver Transplantation for Alcohol‐Associated Liver Disease Does Not Affect Long‐Term Survival: A Case‐Control Study

This study had 42 patients who had alcohol detectable in blood and/or urine matched with 84 controls among patients who received liver transplantation for alcohol-associated liver disease (ALD); this study had a median follow-up of 12.9 years..

Key findings:

  • Long‐term survival was not different between the groups; however, rates of recurrent cirrhosis and cirrhosis‐related deaths were more frequent in the alcohol consumption group
  • Relapse to any alcohol consumption rate was higher in the case group (59.5%) than in the control group (38.1%, odds ratio 2.44; CI95% = [1.13; 5.27]), but sustained excessive consumption was not significantly different between the groups (33.3% versus 29.8% in case and control groups respectively, χ2 = 0.68). 

My take: Yikes.! Fortunately, alcohol consumption is not a significant factor in pediatric liver disease. For adult hepatologists, this study highlights the need for patient support due to the frequency of alcohol relapse.

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Deluge of Liver Disease Due to COVID-19?

Two articles in a recent issue of Hepatology describe both direct and indirect effects of COVID-19 on the liver.

The first study with 2273 patients (MM Phipps et al Hepatology 2020; 72: 807-817. Full Text: Acute Liver Injury in COVID‐19: Prevalence and Association with Clinical Outcomes in a Large U.S. Cohort), with retrospective data, describes how most cases of COVID-19 are mild. Severe cases of liver disease are generally a marker for elevated inflammatory markers and severe systemic disease. Key findings:

  • 45% had mild (ALT <2 x ULN), 21% moderate (ALT 2-5 x ULN), and 6.4% severe liver injury (SLI) (ALT >5 x ULN).
  • Patients with SLI had a more severe clinical course, including higher rates of intensive care unit admission (69%), intubation (65%), renal replacement therapy (RRT; 33%), and mortality (42%).
  • In multivariable analysis, peak ALT was significantly associated with death or discharge to hospice (OR, 1.14; P = 0.044), controlling for age, body mass index, diabetes, hypertension, intubation, and RRT

Going into this new year, the more concerning effects of COVID-19 pandemic for the liver is likely to be the increase is severe chronic liver disease related to alcohol (and perhaps fatty liver disease too). The second article (BL Da et al. Hepatology 2020; 72: 1102-1108. Coronavirus Disease 2019 Hangover: A Rising Tide of Alcohol Use Disorder and Alcohol‐Associated Liver Disease) discusses the expectation of increased liver disease due to alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). Key points:

  • In China, reports indicate a “>2-fold increase in harmful drinking after COVID-19, an effect likely repeated in the United States where an estimated 12.7% of the population has AUD and ALD is responsible for the highest hospitalization cost burden among all chronic liver diseases (CLDs).”
  • Increased alcohol use is likely to worsen other chronic liver diseases in addition to ALD
  • In addition, all of these effects are compounded by avoidance of health care facilities and delays in care

My take: COVID-19 infections have direct effects on the liver. However, the increased use of alcohol as well as weight gain are likely to be more important in terms of liver-related morbidity and mortality.

Improving Fatty Liver Disease Nomenclature

Those who follow this blog regularly know that I have frequently agreed with articles suggesting improving/updating nomenclature for many conditions including the following:

A recent commentary (M Eslam et al. Gastroenterol 2019; 157: 590-3) suggests that fatty liver diseases could use a nomenclature makeover as well.

In pediatrics, the issue of alcoholic and nonalcholic fatty liver disease (NAFLD) overlap is fairly minor in many ways.  In fact, when I am seeing a young teen with NAFLD, parents will often chuckle when I tell them that ‘Johnny’ needs to lay off the booze (now and in the future).  However, it is difficult to fully differentiate nonalcoholic fatty liver disease from alcoholic fatty liver disease, especially in adults.

Full Text: Toward More Accurate Nomenclature for Fatty Liver Diseases

Key points:

  • “Light (1.0-9.9 g/d) or moderate (10.0–29.9 g/d; 10.0–19.9 g/d for women) alcohol consumption in patients with NAFLD is not uncommon…The negative impact of alcohol intake also extends to nonalcoholic steatohepatitis resolution.”
  • “it is time for clinicians to recognize that, within the spectrum of fatty liver disease, there will be patients with true alcohol-related liver disease (AFLD), those with predominant AFLD compounded by metabolic cofactors, those with true NAFLD in whom alcohol consumption is near zero and disease progression is due to metabolic factors, and perhaps a majority with fatty liver disease owing to an abnormal metabolic milieu but with alcohol intake of ≤30 g/d.”
  • ” An updated and more appropriate nomenclature and classification system is required to reflect the nuances of disease etiology within the spectrum of fatty liver disease…”
    • MPFL: metabolic dysfunction predominant fatty liver;
    • APFL, alcohol predominant fatty liver;
    • MPFL/A and MPFL/N: metabolic dysfunction predominant fatty liver with, and without alcohol intake that is anything more than ceremonial
    • APFL/M and APFL/N: alcoholic predominant fatty liver with metabolic dysfunction or with no metabolic dysfunction.

My take: The authors present a good rationale for updating fatty liver disease –will this be adopted?

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Liver Shorts April 2019

CL Mack et al. JPGN 2019; 68: 495-501. This multicenter prospective open-label phase I/III trial of IVIG in biliary atresia patients status-post Kasai indicated that the infusions were tolerated.  However, though this study was not powered to detect efficacy, survival with native liver was LOWER among patients who had received IVIG (n=29): 58.6% compared to the comparison placebo group 70.5% (n=64).  Thus, despite the theoretical advantages of IVIG which targets aspects of the immune system and improvement in a murine model, in practice IVIG does not appear promising for biliary atresia.

D Kim et al. Hepatology 2019; 69: 1064-74. This study shows that despite improvements in hepatitis C mortality rates associated with newer treatments, there is an overall increase in mortality rates from cirrhosis and hepatocellular carcinoma.  This increase is driven by increasing prevalence and severity of both alcoholic liver disease and nonalchoholic fatty liver disease. The overall cirrhosis-related mortality increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3%. Similarly, the overall HCC-related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at annual increase of 2%. The editorial on page 931 (TG Cotter and MR Charlton) notes that each year there are more than 40,000 deaaths associated with chronic liver disease.

H Park et al. Hepatology 2019; 69: 1032-45. This study, using Truven Health MarketScan Cata, examined the outcomes of more than 26,000 patients with newly-diagnosed hepatitis C virus (HCV) infection.  Among the 30% who received oral direct-acting antiviral (DAA) therapy, there were improved outcomes in those with and without cirrhosis. In those with cirrhosis (n=2157), DAA was associated with a 72% and 62% lower incidences of HCC and DCC [decompensated cirrhosis] respectively. In noncirrhotic HCV patients (n=23,948), DAA was associated with a 57% and 58% lower incidence of HCC and DCC respectively.  In addition to improved health outcomes, DAA treatment resulted in decrease health care costs, especially for patients with cirrhosis.

Z Kuloglu et al. JPGN 2019; 68: 371-6.  In this multicenter Turkish study, the authors identified 810 children (median age 5.6 years) with unexplained transaminase elevation (62%),unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%) and cryptogenic fibrosis or cirrhosis (6%).  LAL-D [lysosomal acid lipase deficiency] activity was deficient in 2 siblings (0.2%); both had LDL ~155.  Overall, even in at risk groups, LAL-D is rare.

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Screenshots: Peutz-Jeghers Syndrome, Alcohol #1 for Liver Transplantation, Case report Fanconi Syndrome due to Tenofovir Alafenamide

These images (S Sengupta, S Bose. NEJM 2019; 380: 472) show hyperpigmented macules on the lips, oral mucosa and nose in the first frame, a target sign on CT scan indicative of intussception, and a jejunal resection with polyps that triggered the intussception. Related blog post: Update for Peutz-Jegher Syndrome

Changing Liver Mortality Trends Since 2007

A recent study (D Kim et al. Gastroenterol 2018; 155: 1154-63) used a CDC database which captures >99% of deaths in the U.S. to analyze mortality trends from 2007 through 2016.  Full text link available online: Changing Trends in Etiology-Based Annual Liver Mortality

When looking at all-cause mortality, there has been a significant decline in deaths associated with hepatitis C (HCV) but not in deaths associated with alcoholic liver disease (ALD).  The image below shows the trend and the impact of direct-acting antivirals.  Deaths associated with nonalcholic fatty liver disease (NAFLD) and due to hepatitis B (HBV) are described in this study as well, though both together account for less than 1/4th deaths associated with ALD.  Interestingly, mortality related to NAFLD was increasing slowly over the study period.

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