HPHS Journal Watch: May/June 2022

American Journal of Clinical Pathology

Hepatitic Variant of Graft-vs-Host Disease.

Liang TZ, Dong S, Fang, M, et al. Am J Clin Pathol. 2022 Jun;157(6):948-955.


Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Hepatitic and classic variants have been described predominantly based on clinical factors. Based on a single-institution cohort (50 liver biopsies from 40 patients), this report reports the prevalence of the hepatitic versus classic variants, with a comparison of clinicopathologic features between the two groups. Cases with confounding factors (i.e., infection) were excluded by chart review. 15 cases (30%) were classified as hepatitic variant based on the presence of moderate portal inflammation with interface activity and moderate to marked lobular inflammation; 35 (70%) were classified as classic variant based on mild portal inflammation without interface activity, and absent to mild lobular inflammation. All cases (hepatitic and classic) demonstrated bile duct damage. Ductular reaction, apoptosis, and endotheliitis were more commonly seen in the hepatitic variant with higher median AST and ALT values. Patients with classic variant GVHD more commonly showed higher alkaline phosphatase and bilirubin levels. Hepatocyte ballooning was observed in patients without risk factors for steatohepatitis and its presence was an independent poor prognostic factor. Given that the majority (80%) of cases (classic and hepatitic) occurred >100 days post-transplant, the standard timeframe at which immunosuppressive agents are weaned, the findings suggest that GVHD in the liver may be related to immunosuppressant taper. Normalization of LFTs was significantly longer in the hepatitic variant compared to the classic variant.

American Journal of Surgical Pathology

Hepatic Adenomas in Patients 60 and Older are Enriched for HNF1A Inactivation and Malignant Transformation

Yasir, S, Chen Z, Jain D, et al. Am J Surg Pathol. 2022 June;46:786-792.


Hepatic adenomas are typically a neoplasm of younger adults, but these lesions can rarely be identified in patients over age 60. The authors of this descriptive retrospective study focused on adenomas in older adults to determine if morphologic features and risk of malignancy differed from those found in younger patients. Overall, 26 adenomas in patients over 60 years old underwent histologic review and were compared to 50 adenomas diagnosed in patients aged 31-39 years. The authors found that adenomas in the older age group were more likely to be HNF1a-inactivated (69% vs. 16%) and malignant transformation (23% vs. 6%). They were also more likely to have dense lipofuscin pigment and/or myxoid change. The malignant change in the older age group does not appear to depend on the beta-catenin pathway based on immunostaining patterns in this study.

Clinical Gastroenterology and Hepatology

Prognostic Role of Liver Biopsy in Patients With Severe Indeterminate Acute Hepatitis

Lin S, Araujo C, Hall A, et al. Clin Gastroenterol Hepatol. 2022 May;20(5):1130-1141.e7.


This study evaluated the clinicopathologic features and outcomes in 43 patients with severe acute hepatitis of unknown etiology (severe indeterminate acute hepatitis). Of their cohort, 39.5% underwent liver transplantation and 16.2% died within 3 months. Ductular reaction, ductular cholestasis, and interface inflammation were more common in patients with longer duration of jaundice (>2 weeks). The presence of multilobular necrosis (44.1% of patients) was associated with higher INR and MELD score and was an independent factor associated with death or transplantation. This article proposes a prognostic model incorporating MELD score with presence or absence of multilobular necrosis.


Learning-Based Classification of Hepatocellular Nodular Lesions on Whole-Slide Histopathologic Images

Cheng N, Ren Y, Zhou J, et al. Gastroenterology. 2022 Jun;162(7):1948-1961.


Hepatocellular nodular lesions (HNLs) or well-differentiated hepatocellular lesions pose a diagnostic challenge, particularly on small needle core biopsies. The authors of this study aimed to develop a deep learning system to improve the diagnosis of HNLs (WD-HCC, HGDN, low-grade DN, focal nodular hyperplasia, hepatocellular adenoma) and background tissues (nodular cirrhosis, normal liver tissue). Surgical and biopsy specimens were collected from 6 hospitals. Each specimen was reviewed by 2-3 subspecialists. The study utilized four deep neural networks (ResNet50, InceptionV3, Xception, and the Ensemble) and their performances were evaluated by confusion matrix, receiver operating characteristic curve, classification map, and heat map. The predictive efficiency of the optimal model was compared with that of 9 pathologists. Overall, 213,280 patches were obtained from 1115 whole-slide images of 738 patients. An optimal model was chosen and named hepatocellular-nodular artificial intelligence model (HnAIM), with the overall 7-category area under the curve of 0.935 in the independent external validation cohort. For biopsy specimens, the agreement rate with subspecialists’ majority opinion was higher for HnAIM than 9 pathologists on both patch level and whole-slide images level. Overall, the deep learning diagnostic model for HNLs enhanced the diagnostic rate of early HCC and risk stratification of patients with HNLs.


Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

Mózes FE, Lee JA, Selvaraj EA, et al. Gut. 2022 May 1;71(5):1006-19.


This study aimed to derive diagnostic strategies that could reduce the need for liver biopsies after evaluating the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4), and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS). The authors conducted a patient data meta-analysis (IPDMA) with three main aims: (1) to evaluate the performance of LSM-VCTE and compare it to the performance of FIB-4 and NFS as screening tests to rule out advanced fibrosis, (2) to evaluate NIT combination strategies to minimize the number of cases that would need a liver biopsy in secondary care, and (3) to explore factors that influence diagnostic accuracy. They found that the sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63–68) and 86% (84–87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37–39) and specificity of 90% (89–91) with 19% needing biopsy. These non-invasive test cut-offs can be used for the diagnosis of cirrhosis as this has been validated in a large group of patients. This could lead to a decrease in the need for liver biopsies in secondary care.

Hepatology Communications

Tinospora Cordifolia (Giloy)-Induced Liver Injury During the COVID-19 Pandemic-Multicenter Nationwide Study From India

Kulkarni AV, Hanchanale P, Prakash V, et al. Hepatol Commun. 2022 Jun;6(6):1289-1300.  


This multicenter study from India described clinical and histopathological features of liver injury associated with the use of the herbal supplement Tinospora cordifolia (also known as Giloy or heart-leaved moonseed), including chemical and toxicology analysis. 43 patients were identified who had no identifiable cause for acute liver injury other than Giloy consumption. Patients presented with acute hepatitis, acute worsening of chronic liver disease, or acute liver failure with a median time of 46 days between ingestion to onset of symptoms. The authors report the presence of autoantibodies in 60% of patients, most commonly ANA. Histologic features included necrosis (ranging from spotty to submassive/massive necrosis), portal-based, a mixed pattern of inflammation, and cholestasis.


Hepatocellular adenoma: what we know, what we do not know, and why it matters

Bioulac-Sage P, Gouw ASH, Balabaud C, et al. Histopathology. 2022 May;80(6):878-897.


This review article provides updates on hepatocellular adenoma, including risk factors, diagnosis, classification, risk for bleeding, and progression to hepatocellular carcinoma, as well as hepatocellular adenoma in particular clinicopathological contexts.

Utility of sonic hedgehog and keratin 8/18 immunohistochemistry for detecting ballooned hepatocytes

Kusano H, Kondo R, Ogasawara S, et al. Histopathology. 2022 May;80(6):974-981.


The authors investigated the utility of immunostaining for sonic hedgehog (SHh) protein (positive in ballooned hepatocytes) and Keratin 8/18 (K8/18) (negative in ballooned hepatocytes) in detecting ballooned hepatocytes. Immunohistochemistry for SHh and K8/18 was evaluated in non-tumorous liver tissue from 100 cases of resected hepatocellular carcinoma of various etiology. The degree of hepatocyte ballooning was scored as follows: 0, none; 1, few; 2, many ballooned hepatocytes, based on (H&E) staining only and SHh or K8/18 immunostaining combined with H&E staining. With SHh or K8/18 immunostains, the score of ballooned hepatocytes was upgraded in 20 and 19 cases, and downgraded in none and 2 cases, respectively. The percentage of observed agreement for ballooned hepatocytes scoring was 85% and 92%, and the weighted kappa value was 0.806 and 0.893 with SHh or K8/18 immunohistochemistry. Considering the immunohistochemistry results, background liver disease diagnosis was changed in 15 out of 100 cases (15%) evaluated.

Journal of Hepatology

Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD

Brunt EM, Clouston AD, Goodman Z, et al. J Hepatol. 2022 May;76(5):1030-1041.


This report is the first to assess and quantify interobserver variability in the identification of ballooned hepatocytes using digitized slides by a panel of 9 international expert hepatopathologists. The importance of histologically identified hepatocyte ballooning lies in their use as a key feature to discriminate non-alcoholic steatohepatitis (NASH) from steatosis (non-alcoholic fatty liver, NAFL) and use as a key regulatory-approved surrogate endpoint for drug efficacy. The results of this study showed that there is overall poor interobserver agreement, even amongst expert pathologists with many years of experience, in identification of hepatocyte ballooning. Thus, the presence or complete absence of hepatocyte ballooning may be too subjective to be used as a trial endpoint. Using a concordance threshold of 5 or more pathologists (simple majority; concordance atlas), an artificial intelligence (AI) algorithm (qBallooning2) was optimized, with a sensitivity of 17%. AI assistive technologies may be further helpful in reproducibly quantifying ballooned hepatocytes, but given the wide variation in classification/quantification of ballooned hepatocytes, as demonstrated by this study, creating a human histological reference standard that will produce an error-free classification remains challenging.

Value of liver biopsy in the diagnosis of drug-induced liver injury

Ahmad J, Barnhart HX, Bonacini M, et al. J Hepatol. 2022 May;76(5):1070-1078.


Due to the lack of standardized diagnostic criteria, the diagnosis of idiosyncratic drug-induced liver injury (DILI) remains challenging. The main aim of this study was to determine the utility of liver biopsy in the diagnosis or staging of DILI. The study evaluated data from 50 patients enrolled in the DILI Network (DILIN) who had liver biopsies performed within 60 days of DILI onset; standard DILIN consensus causality scoring was performed for all patients based on 6-month post-injury data (5-point scale; high causality: 1=definite, 2=highly likely, 3=probable; low causality: 4=possible, 5=unlikely) by 3 experienced hepatologists, both before and after review of the liver histology with a hepatopathologist. Of the 50 cases, 42 were high causality; histology review changed the causality score in 68% of patients, with an increase in DILI likelihood in 48% and a decrease in 20%, resulting in a change in diagnostic certainty from less (causality score 3 or 4) to highly certain (1, 2 or 5) in 38% of patients. In 70% of cases, liver histology was considered helpful. Thus, this study demonstrates that liver histologic assessment may help clarify a diagnosis of DILI, and may be particularly helpful in equivocal cases.

Liver Transplantation

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation

Rocque B, Zaldana A, Weaver C, et al. Liver Transpl. 2022 May;28(5):843-854.


Pediatric liver transplantation (LT) generally results in excellent long-term outcomes, but early acute cellular rejection and late graft fibrosis can occur. This article investigated the clinical value of surveillance biopsies (SBs) in pediatric LT. A retrospective cohort of 236 pediatric LT recipients was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). Patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Biopsy was a safe procedure – only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy. SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. In conclusion, SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization.

Low Levels of Hepatocyte-Specific Methylation in Cell-Free DNA Are a Strong Negative Predictor for Acute T Cell-Mediated Rejection Requiring Treatment Following Liver Transplantation

Cox DRA, Low N, Goh SK, et al. Liver Transpl. 2022 Jun;28(6):1024-1038.


“Cell-free DNA” (cfDNA) describes DNA fragments released from the cell into the extracellular space due to active secretion, apoptosis, or necrosis. Tissue-specific DNA methylation patterns enable the identification of the tissue of origin of cfDNA and can be used as a marker for graft-derived cell-free DNA (gdcfDNA). Quantifying graft-specific methylation in cfDNA has a major advantage over previous gdcfDNA techniques: it does not require genotyping/sequencing. This prospective, cross-sectional study investigated the utility of measuring hepatocyte-specific methylation in cfDNA (HS-cfDNA) to quantify gdcfDNA and its accuracy in detecting acute T cell-mediated rejection (ATCMR) following liver transplantation (LT). Blood was collected from LT recipients immediately prior to graft biopsy for suspected rejection. A total of 51 patients were recruited; 37 had evidence of rejection on biopsy and 20 required treatment. HS-cfDNA significantly outperformed LFTs in identifying patients requiring treatment (area under the curve, 73.0%; 95% confidence interval, 55.4%-90.6%; P = 0.01). Low levels of HS-cfDNA were a strong negative predictor for acute T cell-mediated rejection requiring treatment (negative predictive value, 86%) and may have a future role in triaging patients prior to liver biopsies.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Dana Balitzer, MD; University of California San Francisco
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Meredith Pittman, MD; Maimonides Medical Center
Daniel Roberts, MD; Cleveland Clinic
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Xuefeng Zhang, MD; Cleveland Clinic

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