Liver Shorts: May 2019

ED Bethea et al. Clin Gastroenterol Hepatol 2019; 17: 739-47. Using a Markov-based mathematical model, the authors “found transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy to a cost-effective strategy that could improve health outcomes.”

A Villanueva. NEJM 2019; 1450-62. This is a succinct review of hepatocellular carcinoma (HCC). Some points:

  • More than 1 million patients will die from liver cancer in 2030.
  • The rate of death from liver cancer increased 43% from 2000 to 2016,.  The 5-year survival rate is grim at only 18%.  Only pancreatic cancer is more lethal.
  • HCC is rare among patients without preexisting liver disease.  Cirrhosis is the main risk factor, though hepatitis B has direct oncologic effects even in the absence of cirrhosis.
  • The authors note that cancer surveillance has no “high-quality randomized controlled trials.” However, this may be due to difficulties with enrollment. In one study, 99%of patients declined to assume the risk of being randomly assigned to the nonsurveillance group. Nonetheless, mathematical models, and lower quality studies all show survival benefits of surveillance.

Related blog post:

  • Liver Shorts April 2019 Obesity/NAFLD and alcoholic liver disease are driving an increase in HCC and liver cancer mortality

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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Joshua Tree National Park

More Cases of Hepatocellular Carcinoma after Fontan

Several years ago, there were 4 cases of hepatocellular carcinoma (HCC) following Fontan procedure reported in the NEJM. (Reviewed in this blog: Hepatocellular carcinoma after Fontan Procedure).

Another recent report describes 3 patients who presented with HCC more than 10 years after Fontan procedure.  The age of these patients varied from 20 to 28 years. The authors use the term Fontan-Associated Liver Disease (FALD).  They note that FALD is strongly associated with the interval from the procedure, increasing in frequency with more time following surgery.  The risk of FALD is 4.4 times greater between years 11-15 years than in the first 10 years.

The authors recommend screening for HCC in patients 10 years after Fontan procedure. They suggest a baseline MRI followed by biannual ultrasounds and alpha-fetoprotein tests.

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Warren Peak, Joshua Trree National Park

Does Screening for Hepatocellular Carcinoma Improve Outcomes in Patients with Cirrhosis?

Despite widespread recommendations to screen patients with cirrhosis for hepatocellular carcinoma (HCC), a recent study (AM Moon et al. Gastroenterol 2018; 16: 1777-85) found “No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients with Cirrhosis.” The title of the study did not make sense to me based on previous publications that have noted increased risk of HCC in patients with cirrhosis and the presumption that screening would allow effective interventions to prevent death due to HCC.  So I looked at the study a little closer:

Background/Methods: The authors utilized a matched case-control study within the U.S. Veterans Affairs health care system to determine whether ultrasonography (US) or alpha-fetoprotein (AFP) screening was associated with decreased cancer-related mortality.

They identified 238 patients with cirrhosis who died of HCC between 2013-2015 –all of whom had a diagnosis of cirrhosis at least 4 years before the diagnosis of HCC.  Then, they matched them with a control patient with cirrhosis who did not have HCC and had been identified at least 4 years prior to matched case’s HCC.

Key findings:

  • There was no significant difference between the cases and the controls in the proportions who underwent screening:
  • For U/S screening: 52.9% cases and 54.2% for controls.
  • For AFP (serum) screening, 74.8% vs 73.5% respectively.
  • For either U/S or AFP screening, 81.1% vs 79.4%.
  • For both U/S and AFP screening, 46.6% vs 48.3% respectively.
  • Table 4 provides odds ratios and adjusted odds ratios for the cases compared to controls.  The Adjusted Odds ratios for U/S 0-4 years before index case was 0.95, for AFP 1.08, and for either U/S or AFP 1.11.

The authors found that HCC screening with U/S and/or AFP was not associated with decreased risk of HCC-related mortality.

In their study, the authors note that most studies on HCC screening have been observational which have numerous limitations including lead-time biases (which can overestimate the benefits of screening) and patient selection.  Two randomized controlled trials reached conflicting conclusions; these trials were conducted in China where HCC is mainly associated with hepatitis B infection.

The authors point out that liver societies like AASLD and EASL have recommended U/S every 6 months with or without AFP measurements for HCC surveillance in patients with cirrhosis.  However, non-liver societies have NOT “endorsed HCC screening because of the lack of high-quality data.”  Neither the US Preventive Services Task Force nor the American Cancer Society make recommendations for HCC screening.  And, “the National Cancer Institute found no evidence that screening decreases mortality from HCC but did find evidence that screening could result in harm.”

Strengths of this study:

  • All VA patients have access to medical care; this limits bias due to access to HCC screening
  • The matched-case control design with random controls across a system that delivers care to 8 million veterans across the country indicates that the findings are likely  “typical of community-based settings” and likely to yield “estimates of the impact of screening …[that] approximates the results that would be expected from a randomized controlled trial”

Why Have Previous Studies Indicated that HCC Screening is Worthwhile?

  • According to the authors, even though HCC detected by screening is on average detected at an earlier stage than those detected due to symptoms, “this does not prove that screening leads to earlier detection. Another explanation is that screening is more likely to identify slow-growing tumors, which have a lower stage, and more likely to miss the fast-growing tumors, which are identified at a higher stage by symptoms.”
  • “It is possible that the HCCs most likely to lead to death are the HCCs least likely to be identified by current screening modalities at an early stage.”
  • In addition,  “whether early treatment for HCC in patients with cirrhosis leads to a decrease in case fatality is questionable.”  Patients who receive surgical resection or locoregional treatments remain at risk for recurrent HCC, new HCC and progressive liver dysfunction.  While liver transplantation can cure HCC and cirrhosis, only a “small minority of patients with HCC undergo liver transplantation.”  In 2012, only 1,733 patients received liver transplantation for HCC out of a reported 24,696 incident cases.

My take: This study offers a lot of insight regarding HCC screening and questions its usefulness, though I doubt this study will change how most hepatologists practice.

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Near Banff

 

Hep B-related Hepatocellular Carcinoma in Kids: 8 Needles in 4 Haystacks

Over a 25-year period, investigators (DB Mogul et al. JPGN 2018; 67: 437-440) from 4 medical centers identified 8 patients (8-17 years) with hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV).

The authors indicate that all of the cases were thought to have acquired HBV via vertical transmission.

Key features:

  • 3 were asymptomatic; 50% reported abdominal pain
  • Only 1 case presented to a hepatologist
  • 4 patients had ALT values <1.5 times the upper limit of normal
  • Among those with documented HBeAg (n=3), all were negative and all were positive for anti-HBeAb
  • Alphafetoprotein was elevated in 3 patients, normal in 2 patients and not documented in 3 patients.

My take: HCC rarely occurs in children with HBV.  The most effective way to reduce HCC is through prevention, particularly vaccination.  The role of regular imaging which could detect tumors earlier remains unclear (in the absence of a risk factor like cirrhosis); in this series, only one patient presented to a hepatologist.

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Lake Agnes, Banff

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

Related blog entries:

 

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.

Liver Articles: Short Takes

DBE van Wessel et al. JPGN 2017; 65: 370-74.  This retrospective study showed an increase in biliary atresia incidence in preterm infants compared with full-term: 1.06 per 10,000 compared with 0.52/10,000. In addition, 4-year transplant-free survival rates were significantly worse at 21%, whereas 4-year survival rates was 61%. Clearance of jaundice (with Kasai) was achieved in only 23%.

Related post: Biliary Atresia More Common in Preterm Infants

ES Björnsson et al. Clin Gastroenterol Hepatol 2017; 15: 1635-36. This study examined response to steroids in 18 patients with drug-induced autoimmune hepatitisKey findings: 14 patients had elevated antinuclear antibodies & there were none with elevated smooth muscle antibodies. Infliximab was most frequent agent (n=11) and nitrofurantoin was other frequent agent (n=3).  Overall, 40% improved after discontinuation of medication, the remainder had prompt responses to corticosteroids.  Relapse did not occur when corticosteroids were discontinued.  Among the infliximab group, there was no evidence of liver injury after transitioning to alternative tumor necrosis factor-α inhibitor.

M Balwani et al. Hepatology 2017; 66: 1314-22. Acute Hepatic Porphyrias -Review. Current recommendations include gene sequencing to confirm all biochemical cases. Biochemical tests are spot urine testing of porphobilinogen (PBG), 5-aminolevulinic acid (ALA), and porphyrins. A normal urine PBG in symptomatic patients “excludes the three most common acute hepatic porphyrias.”  For those with abnormal studies, this reference is a handy.

S Wirth et al. Hepatology 2017; 66: 1102-10.  This study examined the effectiveness of sofosbuvir and weigh-based ribavirin dosing in 12-17 year olds with genotype 2 & 3 Hepatitis C infection.  Duration of treatment was 12 weeks for genotype 2 and 24 weeks for type 3.  Overall, SVR12 was achieved in 51 of 52 (98%); one patient with genotype 3 did not achieve SVR12.

Related post: New HCV Treatment Effective in Adolescents (Genotype 1 study)

F Kanwal et al. Gastroenterol 2017; 153: 996-1005. This study, a retrospective cohort of 22,500 VA patients treated for hepatitis C infection, showed that direct-acting antivirals (DAAs) lowered, but did not eliminate, the risk of hepatocellular carcinoma (HCC). Among the 87% who achieved an SVR, the adjusted hazard ratio for HCC was 0.28.  This was true as well as among patients with cirrhosis.. Hazard ratio for those with compensated cirrhosis was 0.32 compared with 0.18 among those without cirrhosis.