Clinical Gastroenterology and Hepatology
Steatosis: A Systematic Review and Meta-analysis.
Verhaegh
P, Bavalia R, Winkens B, et al. Clin Gastroenterol Hepatol. 2018;16(6):837-861.
This
systematic review and meta-analysis studied whether noninvasive tests can
differentiate nonalcoholic steatohepatis (NASH) from simple steatosis (SS).
There were 122 studies evaluating 219 different blood markers and 22 other
tests. Alanine aminotransferase had a pooled sensitivity of 63.5% and specificity
of 74.4% to diagnose NASH. Ferritin had pooled sensitivity of 79.1%,
specificity of 71.9%, and adinopectin had pooled sensitivity of 72.0% and
specificity of 75.7%. The cleaved CK18-M30 as an assay had a pooled sensitivity
of 68.4% and specificity of 74.2%. Of –omics approaches, the GlycoNASH test
data had a pooled sensitivity of 67.1% and specificity of 63.8%. Scoring
systems that combined blood markers, such as NASHTest (combining 10 markers
with age, gender, weight, height, and SteatoTest positivity) showed specificity
of 95.3% but sensitivity of 22.9% in differentially NASH from borderline NASH
and SS. In summary, none of the pooled markers showed both sensitivity and
specificity over 80%. More standardized study designs are needed as the
majority of the studies contained only limited numbers of patients with
significant fibrosis or did not provide the stages of fibrosis.
Acetaminophen-induced
Acute Liver Failure Is More Common and More Severe in Women.
Rubin
JB, Hameed B, Gottfried M, et al; Acute Liver Failure Study Group. Clin
Gastroenterol Hepatol. 2018;16(6):936-946.
Acetaminophen
overdose is the leading cause of acute liver failure (ALF) and acute liver
injury (ALI), accounting for approximately 50% of all ALF cases. Previous data
regarding drug-induced liver injury have shown that women are noted to be at
increased risk for progressing to ALF and require subsequent transplant. From a
national registry of 32 academic medical centers, 1162 patients with
acetaminophen induced ALI (22%) or ALF (78%) were identified. Their
presentation, clinical course, and overall survival between genders were
studied. Sixty-eight percent (170) of acetaminophen induced ALI and 76% (864)
of ALF patients were women. About half of patients with ALF had unintentional
acetaminophen overdose and 40% were suicide attempts. More women than men
co-ingested acetaminophen with sedating agents such as opioids or
benzodiazepines (70% vs. 52%). On presentation, men had higher ALT, bilirubin,
albumin, and MELD scores than women, but otherwise, weight-adjusted ALT was
similar. More women had severe clinical
courses, including severe hepatic encephalopathy (68% women vs. 58% men), and need for critical care needs. However, transplant-free survival were similar between male and females.
https://www.ncbi.nlm.nih.gov/pubmed/29199145
Excellent
Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular
Carcinoma to Within Milan Criteria: A Multicenter Study.
Mehta
N, Guy J, Frenette CT, Dodge JL, et al. Clin Gastroenterol Hepatol. 2018;16(6):955-964.
This
was a multi-center study using a standardized down-staging protocol (within
Milan criteria) to assess outcomes of liver transplantation in such patients. The
type of local regional therapy (LRT) was not standardized. Most received TACE
alone or in combination with radio-frequency ablation.16% of patients were not down-staged
to within Milan criteria. A factor predicting inability to achieve tumor
down-staging was pre-treatment AFP≥1000. The number, size of tumors, MELD
score, number of LRT sessions were not significant predictors of inability to
be down-staged. Successful down-staging to Milan criteria was achieved in 83.4%
(median 2.7 months). Majority were down-staged after a single LRT. Of those who
were down-staged, 17% (28 of 156) had subsequent tumor progression and were
dropped out of the waitlist. 58% of patients received liver transplant.
Following transplant, the explanted liver showed tumor staging within Milan
criteria in 45.9% of cases (T1/T2); 19.3% of cases turned out to be understaged
by imaging and beyond Milan criteria (T3/T4). Median post-LT follow up was 4.3
years with a survival of 95% at 1 year and 80% at 5 years. HCC recurrence
developed in 10% of patients at a median of 19.1 months from transplant.
Predictors of recurrence included an AFP >500 and vascular invasion. Down-staging
resulted in excellent overall 5-year post-LT survival of 80% and recurrence
free probability of 87%. Only 7% had micro- or macro-vascular invasion.
Treatment failure predictors included a pretreatment AFP of >1000 and
Child’s B/C cirrhosis, suggesting that these patients should not be subjected
to the risks of LRT.
Journal of Hepatology
Development
of the liver: Insights into organ and tissue morphogenesis
Ober
EA, Lemaigre FP. J Hepatol 2018; 68
(5):1049-1062.
Employing
the burgeoning modality of three dimensional imaging and distinct model
organisms, this study illustrates the growing understanding of morphogenetic
processes in the adult liver. Stages from
endodermal budding giving rise to an asymmetric liver, mechanisms leading to
liver and lobe development, morphogenesis of the intra and extrahepatic bile
ducts, its reaction to injury, and vascular development are discussed.
Characterization
of liver injury induced by cancer immunotherapy using immune checkpoint
inhibitors
De
Martin E, Michot JM, Papouin B, et al. J Hepatol 2018; 68 (6): 1181-1190.
The
goal of this large scale and well organized study was to accurately evaluate
the incidence of hepatic immune related
adverse events (IRAEs) in patients with metastatic cancer treated with
anti-cancer anti-PD-1, anti-PDL1, and anti-CTLA-4 immunotherapy. Using data gathered in 1,425 patients from
August 2015 to August 2017 by the REISAMIC pharmacovigilance register,
individuals who developed grade ≥3 hepatitis were identified according to the
Common Toxicity Criteria for Adverse Events (CTCAE). The severity of liver injury was classified
according to the Drug-Induced Liver Injury Network (DILIN) 5-point scale. Acute hepatitis due to cancer immunotherapy
was reported in only 3.5% of treated patients.
Two distinct types of immune mediated hepatitis were described: granulomatous hepatitis with fibrin depositis
associated with anti-CTLA-4 mABs; and lobular, non-granulomatous hepatitis
associated with anti-PD-1/anti-PDL1 mABs.
The authors concluded that liver biopsies have a key role in detailing
the severity of injury and in providing guidance in treatment choices.
https://www.ncbi.nlm.nih.gov/pubmed/29427729
Genomic
characterization of biliary tract cancers identifies driver genes and
predisposing mutations.
Wardell
CP, Fujita M, Yamada T, et al. J Hepatol 2018; 68 (5): 959-969.
Biliary
tract carcinomas (BTCs) are a heterogenous group frequently exhibiting poor
response to treatment. This study is a
large-scale genome sequencing analyses of somatic and germline driver events
and genomic landscape mapping to enhance comprehension of carcinogenesis,
better classify, and improve treatment strategies of BTCs. 412 BTC samples were analyzed by whole-exome
sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing using
subtypes of intrahepatic cholangiocarcinomas (ICCs), distal cholangiocarcinomas
(DCCs), peri-hilar type cholangiocarcinomas (PHCs), and gallbladder or cystic
duct cancers (GBCs/CDCs). 32 significantly and commonly mutated genes including
TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some negatively affecting
prognosis, were identified. A novel deletion of MUC17 at 7q22.1 affected
patient prognosis. Cell-of-origin predictions using WGS and epigenetic features
suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline
mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or
MSH2 were detected in 11% (16/146) of BTC patients. Learn more and read about BTCs and their
distinct genetic features including somatic events and germline predispositions.
https://www.ncbi.nlm.nih.gov/pubmed/29360550Modern Pathology
Hepatotoxicity
of immune checkpoint inhibitors: a histology study of seven cases in comparison
with autoimmune hepatitis and idiosyncratic drug-induced liver injury.
Zen
Y, Yeh MM. Mod Pathol 2018; 31: 965–973.
The
authors reviewed adverse effects of immune checkpoint inhibitors in liver and compared
clinicopathologic features between checkpoint inhibitor-induced liver injury
and acute autoimmune hepatitis or idiosyncratic drug-induced liver injury. They
have seven patients treated with nivolumab (n = 5) or ipilimumab (n = 2).
They also performed IHC for B and T cell markers and found large numbers of
CD3+ and CD8+ lymphocytes in immune checkpoint inhibitor treated livers. CD20+
B cells and CD4+ T cells were fewer in checkpoint inhibitor-induced liver
injury than in autoimmune hepatitis or drug-induced liver injury. They conclude
that liver injury caused by cancer immunotherapy shares some features with
autoimmune hepatitis; however, there are obvious differences between the two
conditions.
https://www.ncbi.nlm.nih.gov/pubmed/29403081Journal of Gastroenterology and Hepatology
Individual and combined
effects of hepatitis B surface antigen level and viral load on liver cancer
risk
Yang Y, Gao J, Tan YT, et
al. J
Gastroenterol Hepatol 2018 ;33(5):1131-1137.
Hepatitis
B surface antigen (HBsAg) and viral load are both hallmarks of hepatitis B
virus (HBV) infection. The authors carried out a nested case–control study
including 211 liver cancer cases and 221 controls who were seropositive for
HBsAg within two population‐based cohorts. They found
that elevated levels of HBV‐DNA and HBsAg are associated
with increased risks of liver cancer. Compared with subjects with HBV‐DNA < 2000 IU/ml, the adjusted ORs increased from 2.11
(95%CI: 0.99–4.50) to 10.47 (95%CI: 5.06–21.68) for those with HBV‐DNA level at 2000–19 999 to ≥ 20 000 IU/ml. Compared with
subjects at a low level of HBsAg (0.05–99 IU/ml), the adjusted ORs increased
from 1.82 (95%CI: 0.90–3.68) to 2.21 (95%CI: 1.10–4.43) for those with HBsAg
level at 100–999 to ≥ 1000 IU/ml.
https://www.ncbi.nlm.nih.gov/pubmed/29065440Histopathology
Histological assessment of
the liver explant in transplanted hepatitis C virus patients achieving
sustained virological response with direct-acting antiviral agents.
Putra J., Schiano TD.,
Fiel MI. Histopathol 2018;72(6):990-996.
Direct-acting antiviral
agents (DAAs) have transformed the management of patients with chronic
hepatitis C virus, and treatments are now associated with sustained virological
response (SVR) rates of > 95 %. With
the success of DAAs, histologic examination for hepatitis C has, at least
anecdotally, become less commonplace.
This study evaluated the histologic findings of both inflammation and
fibrosis, of HCV patients who achieved SVR after receiving DAA treatment and compared
them to the histologic findings of a control group of HCV patients who did not
achieve SVR and did not receive DAA treatment.
The authors report a lack of demonstrable association between histologic
findings and SVR status and persistent inflammation in HCV patients with SVR
despite receiving DAAs.
https://www.ncbi.nlm.nih.gov/pubmed/29235144
Increased expression of
senescence-associated cell cycle regulators in the progression of biliary
atresia: an immunohistochemical study.
Sasami M, Kuo FY, Huang
CC, et al. Histopathol 2018;72(7):1164-1171.
Cellular senescence plays
a role in the pathogenesis of various non-neoplastic diseases, including
primary biliary cholangitis and other adult cholangiopathies. This study investigated the role of cellular
senescence, through established senescence markers p16, p21, and NCAM, in
patients with biliary atresia, the most common form of pediatric obliterative
cholangiopathy. The study examined
expression of these markers in bile ducts and bile ductules at early (Kasai
procedure) and late (transplant) stages of biliary atresia and compared them to
a normal control group. Study findings
indicate that increased expression of senescence regulators may be involved in
the progression of biliary atresia in a manner similar to that observed in adult
cholangiopathies.
https://www.ncbi.nlm.nih.gov/pubmed/29392752American Journal of Pathology
Understanding Liver Regeneration: From Mechanisms to
Regenerative Medicine.
Gilgenkrantz H, Collin de l’Hortet A. Am J Pathol 2018;
188(6): 1316-1327.
This review article summarizes the published data in the
past five years in liver regeneration, discussing the mechanisms leading to
regeneration disruption in chronic liver diseases.
https://www.ncbi.nlm.nih.gov/pubmed/29673755Human Pathology
DJ-1 is a useful biomarker for invasive extrahepatic
cholangiocarcinoma.
Tabata Y., Nakanishi Y., Hatanaka Y., et al. Hum Pathol. 2018;76:28-36.
Through a liquid -chromatography mass spectrometry-based
proteomics approach, the authors previously reported that DJ-1 protein is
up-regulated in cholangiocarcinoma compared with non-neoplastic bile duct
epithelium. Building on those findings,
the authors evaluated expression of DJ-1 in patients with invasive extrahepatic
cholangiocarcinoma (EHCC) by evaluating immunohistochemical (IHC) staining for
anti–DJ-1 antibody and the impact of IHC staining score on postoperative
survival. Additionally, serum levels of
DJ-1 in invasive EHCC patients with and without metastasis were compared. Although limited by the number of patients
studied, DJ-1 protein in IHC staining and serum examinations may offer a
biomarker for prognosis in patients with invasive EHCC.
https://www.ncbi.nlm.nih.gov/pubmed/29447925
Low-level clonal FGFR2 amplification defines a unique
molecular subtype of intrahepatic cholangiocarcinoma in a Chinese population.
Pu XH., Ye Q., Yang J., et al. Hum Pathol. 2018; 76:100-109.
Chromosomal translocations and amplifications of the
fibroblast growth factor receptor 2 (FGFR2) locus are present in several tumor
types, including intrahepatic cholangiocarcinoma (ICC). Multiple clinical trials are under way for
repurposing the drugs that target the FGF signaling pathway as an innovative
ICC treatment. In Western countries,
the frequency of FGFR2 fusions in ICC
ranges from a reported 7%-45%. This
study assess the incidence of FGFR2 aberrations, including translocations and
amplification, in Chinese patients. 122
ICCs were evaluated for translocations and amplifications of FGFR2 by
fluorescence in situ hybridization as well as protein expression by
immunohistochemistry. The relationship
between genetic aberrations and protein expression were then compared to
clinicopathologic characteristics and prognostic outcomes. Molecular aberrations were identified in
23/122 (19%) of tumors. Low-level
amplification of FGFR2 was twice as common as FGFR2 translocation; and these
tumors were generally of lower stage and associated with better overall
survival.
https://www.ncbi.nlm.nih.gov/pubmed/29514108
Prepared by:
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; Mayo Clinic, Rochester
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Cynthia Guy MD; Duke University
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Eric Yee MD; University of Arkansas for Medical Sciences
Maria Westerhoff MD; University of Michigan
