Tag Archives: hepatocellular carcinoma

Liver Updates: Statin Protection from HCC, PSVD -new name, novel finding and Hypothyroidism with Hepatic Hemangiomas

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B Zou et al. Clin Gastroenterol Hepatol 2023; 21: 435-444. Open Access! Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease

This study, in agreement with prior studies of individuals with chronic liver disease, showed that statin use is associated with a lower risk of hepatocellular carcinoma in NAFLD as well, with a Hazard Ratio of 0.47 in a database with 272,431 adults with NAFLD. The authors note the concern about hepatotoxicity from statins; however, “severe liver injury from statins is fairly low. Indeed, the incidence of lovastatin-associated fulminant liver failure is about 2 in a million users.”

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J Shan et al. Hepatology 2023; 77:501-511. Open access! Genetic predisposition to porto‐sinusoidal vascular disorder: A functional genomic‐based, multigenerational family study

Porto‐sinusoidal vascular disorder (PSVD; also previously described as idiopathic noncirrhotic portal hypertension [NCPH]…”is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases.”

Key findings:

  • In a group of 4 patients, a novel heterozygous mutation in the FCHSD1 gene was identified but not in 2 familial controls.
  • When this variant was introduced in mice using CRISPR, ” Nine out of the 15 mice carrying the human FCHSD1 R183W variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein.”
  • Aberrant FCHSD1 structure and function led to mTOR pathway overactivation

Related blog post: Time to Adjust the Knowledge Doubling Curve in Hepatology

MA Siano et al. JPGN Reports. 2022; 3(4):p e270,.  Consumptive Hypothyroidism due to Hepatic Hemangiomas: A Case Series and Review of the Literature

“Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to thyroid hormone inactivating enzyme type 3 (Deiodinase) overexpressed by hepatic/hepatic and cutaneous hemangiomas, and occasionally by some other extrahepatic visceral hemangiomas…Pediatric hepatologists should recognize the importance of periodical assessments of thyroid function in patients with hepatic hemangiomas”

“MRI of the abdomen in one of our patients (patient 1), before (A) and after (B) 19 months of treatment with propranolol/10 months of treatment with levothyroxine. The T2-weighted axial MRI images shows the regression of a diffuse infantile hepatichemangioma with innumerable T2 hyperintense masses throughout the liver with central hypointense central regions.”

Should All Pediatric Patients with Hepatitis B Undergo Routine Surveillance for Hepatocellular Carcinoma?

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C Rajan et al. JPGN Reports: November 2021 – Volume 2 – Issue 4 – p e124. Open Access: Hepatocellular Carcinoma in the Absence of Cirrhosis in a Child With Inactive Chronic Hepatitis B Infection

In this case study, the authors “describe an unusual case of a child with chronic hepatitis B infection who developed HCC in the absence of active hepatitis or cirrhosis.” Based on their case report, they advocate for “regular HCC surveillance for all children with chronic hepatitis B, regardless of presence or absence of hepatitis or cirrhosis.”

However, the authors suggestions to expand surveillance to all children with hepatitis B is NOT aligned with current expert opinion (by most experts). This potential recommendation deserves (deserved) more commentary in their discussion. The AASLD recommends offering surveillance when the risk of HCC is at least 1.5% per year and the incidence is greater than 0.2% per year, which includes patients with cirrhosis and some non-cirrhotic hepatitis B carriers [7]. In a study from Taiwan (blog post: HBV Vaccination Prevents Cancer), the authors showed the beneficial effects of vaccination: HCC incidence per 105 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. This study also showed how rare HCC cases are in children; thus, showing benefit of vaccination was impressive.

The AASLD guidelines on HCC (Link to PDF: Diagnosis, Staging, and Management of
Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for
the Study of Liver Diseases) notes the following high risk categories:

My take: This case report is helpful in emphasizing the risk of HCC in patients with HBV, even in those without significant risk factors. However, at this time most experts do not recommend surveillance in those with a low risk of developing HCC.

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Liver Shorts -May 2020 & CDC Recommendations for Office (NY Times Summary)

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NY Times:  C.D.C. Recommends Sweeping Changes to American Offices

FDA Approves Hepatitis C Pangenomic Treatment for Children (Mar 19, 2020):

The U.S. Food and Drug Administration today approved a supplemental application for Epclusa (sofosbuvir and velpatasvir) to treat hepatitis C virus (HCV) in children ages 6 years and older or weighing at least 37 pounds (17 kilograms) with any of the six HCV genotypes—or strains—without cirrhosis (liver disease) or with mild cirrhosis.

Review: NAFLD in China 1999-2018 J Zhou et al. Hepatology 2020; 71: 1851-4.

  • NALFD increased by 8-9% in prevalence, to 29.1%.  This means there are more than 230 million individuals with NAFLD in China.

Use of HCV-positive donors for liver transplantation to HCV-negative recipients. N Anwar et al. Liver Transplantation 2020; 26: 673-80. Key finding: HCV-positive organs had similar outcomes regarding graft function, patient survival and post-LT complications.

Recent Decline in Hepatocellular Carcinoma Rates in U.S. MS Shiels, TR O’Brien. Gastroenterol 2020; 158: 1503-5. Using SEER-21 population based cancer registries covering 37% of U.S. population, the authors found a recent decline in rates of HCC:

  • 2000-2016: 119,078 cases of HCC in SEER-21 registries, 5.84/100,000
  • Rates increased b 5.6% per year from 2000-2007, then by 2.7% per year from 2007 to 2013, subsequent rate reached a plateau and declined with drop of 1.4% per year (P=.12)
  • Improvement could have been due in part to improvement in viral hepatitis treatment; a less favorable explanation could be that the drop occured due to a death from another cause (eg. non-HCC death due to cirrhosis, opioid-related death

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Potential Treatment for Nonalcoholic Steatohepatitis N Chalasani et al. Gastroenterol 2020; 158: 1334-45. The study explored the use of Belapectin, an inhibitor of Galectin-3, in patients with nonalcoholic steatohepatitis and cirrhosis. n=162, phase 2 randomized, double-blind study. Key finding: 1 year of every 2 week infusions were safe but not associated with significant reductions in hepatic venous pressure gradient (HVPG) or fibrosis. However, in a subgroup without varices, there was lowered HVPG and lowered risk of new varices.

Treatment Options for Minimal Hepatic Encephalopathy:  RK Dhiman et al. Clin Gastroenterol Hepato 2020; 18: 800-12.  This meta-analysis which included 25 trials (n=1563) found the following:

  • For reversing minimal hepatic encephalopathy (MHE), rifaximin (OR 7.53) and lactulose  (OR 5.39) were effective with moderate quality evidence.  Probiotics had OR 3.89 and L-ornithine L-aspartate had OR 4.45 —both with low quality evidence.
  • For prevention of HE, L-ornithine L-aspartate had OR 0.19 (‘high moderate’ quality), and lactulose had OR 0.22 (moderate quality) were effective. Probiotics had OR 0.27 with low quality evidence.
  • The authors conlude that lactulose is the most effective agent for prevention and reversal of MHE.

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Curbside Humor

 

Is Tenofovir the Best Medication for Hepatitis B Infection?

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Two recent studies have suggested that tenofovir may be more effective for hepatitis B virus (HBV) infections.

  • T C-F Yip et al. Gastroenterol 2020; 158: 215-25.
  • J Choi et al. JAMA Oncol 2019; 5: 30-6. (Reviewed in a commentary by P Lampertico, M Colombo. Gastroenterol 2019; 157: 1682-88)

In the first retrospective study from Hong Kong, the authors analyzed 29,350 consecutive treated-patients  (mean age 52.9 years).  1309 were treated with tenofovir disoproxil fumarate (TDV) and 28,041 were treated with entecavir. Key findings:

  • TDF-treated patients were younger (mean age 43.2 years vs. 53.4 years) and had less cirrhosis at baseline (2.9% vs. 13.6%).
  • After a median follow-up of 3.6 years, 8 TDF-treated patients (0.6%) and 1386 (4.9%) of entecavir-treated patients developed hepatocellular carcinoma (HCC).  The authors note that TDF maintained a lower rate of HCC after propensity score weighting (hazard ratio of 0.36)

The second study was a nationwide population cohort database with >24,000 patients –all with ALT >80. Key finding:

  • HCC was significantly lower in TDF group than in the entecavir group, the percent person-years being 0.64 compared to 1.06; though, there was not a lower mortality rate or a lower liver transplantation rate.

The commentary associated with the latter study makes the following points:

  • Both TDF and entecavir could prevent “the incidence and mortality of HCC …in >85% of patients who received [them] for years.”
  • Studies comparing TDF and entecavir have come up with conflicting results.  “Three studies in Korea, the U.S, and Europe reported no differences between NAs even after patient matching by a propensity score.”
  • “Cumulatively, all these studies deliver the reassuring message of a robust risk reduction of liver cancer taking place in patients with chronic hepatitis B who experience prolonged virus suppression after NA therapy, but currently they fail to provide convincing evidence that one NA is superior to the other one in determining such clinical benefit.”

My take: Tenofovir may be better but the answer is not definitive; due to lack of randomization, there may still be confounding variables in which sicker patients are receiving entecavir and this could be contributing to the difference in outcomes.  Also, in patients with bone disease and renal impairment, tenofovir alafenamide (TAF) or entecavir is recommended.

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From P’tit Train Du Nord Linear Park

Liver Briefs -July 2019

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NH Ebel et al. JPGN 2019; 68: 788-92.  Hepatic venous pressure gradient (HVPG) did not correlate with the risk of complications from portal hypertension in this pediatric cohort (n=41); this is in contrast to studies in adults showing the utility of HVPG measurements.

AG Singal et al. Gastroenterol 2019; 156: 2149-57. AGA Practice Update on Direct-Acting Antivirals for Hepatitis C and Hepatocellular Carcinoma. There are 12 best practice advice –here are the first three:

  • BEST PRACTICE ADVICE 1: DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.
  • BEST PRACTICE ADVICE 2: Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment.
  • BEST PRACTICE ADVICE 3: Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance

N Hamdane et al. Gastroenterol 2019; 156: 2313-29. This study found that chronic HCV infection induced specific genome-wide-changes in H3K27ac which correlated with expression of mRNAs and proteins.  These epigenetic changes persisted after an SVR to DAAs or interferon-based therapies. These changes could explain some of the reason why HCC remains a risk after successful treatment with DAAs.

DT Dieterich et al. Gastroenteroloy & Hepatology 2019; 15S: 3-11 Link: “A simplified algorithm for the management of Hepatitis C Infection”  An excerpt:

“The algorithm begins with universal HCV screening and diagnosis by testing for HCV antibody with reflex to polymerase chain reaction to detect HCV RNA. The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. Unless clinically indicated, on-treatment monitoring is optional. Confirmation of cure (undetectable HCV RNA 12 weeks posttreatment) is followed by harm-reduction measures, as well as surveillance for hepatocellular carcinoma every 6 months in patients with advanced fibrosis/cirrhosis.”  My take: This algorithm is much simpler than the expanded recommendations from HCVguidelines.org website, though these agents, to my knowledge, do not yet have a pediatric indication.

 

Liver Briefs -June 2019 part 2

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E Cowell et al. JPGN 2019; 68: 695-99. This study reviewed 61 cases of pediatric hepatocellular carcinoma to determine predisposing conditions  (in Houston TX).  The majority did NOT have recognizable predisposing conditions.  25 of 61 (41%) had a predisposing condition including cryptogenic cirrhosis/steatosis (9), genetic (7), biliary pathology (4), viral hepatitis (1), and other (4).  Those without a recognizable predisposing condition were diagnosed later and with more advanced disease/decreased survival.

VA McLin et al. JPGN 2019; 68: 615-22. Useful review on congenital portosystemic shunts.

DE Kaplan et al. Gastroenterol 2019; 156: 1693-1706. This large study form the VA with more than 70,000 patients examined the relationship between statin exposure and survival in patients with cirrhosis.  “Each cumulative year of statin exposure was associated with an independent 8-8.7% decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and B.”

AG Singal et al. Gastroenterol 2019; 156: 1683-1692. Direct-acting antiviral therapy was not associated with recurrent hepatocellular carcinoma (HCC) in a multicenter cohort study with 793 patients with HCV-associated HCC. Thus, DAAs appear safe in patients who have achieved a complete response to HCC Rx

Liver Shorts: May 2019

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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

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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

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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