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

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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.

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.

Autoimmune Hepatitis and Hepatocellular Carcinoma

Briefly noted:

A Tansel et al. Clin Gastroenterol Hepatol 2017; 15: 1207-17.  This systematic review and meta-analysis identified 25 studies and 6528 patients examining the relationship between autoimmune hepatitis (AIH) and hepatocellular carcinoma (HCC) .  In these studies the median followup was 8.0 years.  Key findings:

  • The pooled incidence of HCC was 3.06 per 1000 patient-years
  • 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their diagnosis

My take: This study demonstrates that AIH patients with cirrhosis are at increased risk for HCC.  In patients with AIH who do not have cirrhosis, there does not appear to be a significant risk of HCC.

Also: Link for Online Resource for Hepatopulmonary Syndrome (Canadian Sponsored site). This site has content for patients and for practitioners, including a useful video.

 

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Increasing Incidence of Hepatocellular Carcinoma in the U.S.

A recent study (DL White et al. Gastroenterol 2017; 152: 812-20) provide data showing a striking increase in the incidence of hepatocellular carcinoma (HCC). Using data from the US Cancer Statistics Registry which covers 97% of U.S. population, the authors found the following:

  • HCC incidence rose from 4.4 per 100,000 in 2000 to 6.7 per 100,000 in 2012
  • The annual rate of increase was 4.5% from 2000-2009, but then 0.7% annually from 2010-2012
  • The greatest increase occurred in 55-59 year olds (8.9% annually) and 60-64 year olds (6.4% annually)

The main HCC risk factors are HCV, HBV, and alcoholic liver disease, though obesity-associated HCC is emerging as an important risk factor as well.  The highest rates of HCC are seen in southern and western states, with Texas having the highest rates overall.  The high rate in Texas is in part due to the higher rates of HCC in Hispanics.

Overall, the authors indicate that the rising HCC rates are most closely tied to the peak HCV cohort (1945-65) and speculate that the arrival of direct-acting antivirals may help. At the same time, this HCV cohort is composed “disproportionately [of] minorities and of lower socioeconomic status” and may have less access to these advances in treatment.  Furthermore, in states like Texas which did not adopt Medicaid expansion as part of the Affordable Care Act, there are more uninsured patients who will be less likely to identify preceding risk factors for HCC.

My take: Perhaps in 20 years, we will see HCC incidence maps that are improving as HCV treatments become more widely available.  This presumes that other HCC risk factors, including obesity and alcohol, do not worsen significantly.

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