HPHS Journal Watch:  May/June 2023 

American Journal of Gastroenterology 

Prevalence of Celiac Disease in Patients With Liver Diseases: A Systematic Review and Meta-Analyses 

Yoosuf S, Singh P, Khaitan A, et al. Am J Gastroenterol. 2023 May 1;118(5):820-832.  


The authors performed a systematic review with meta-analyses to estimate the pooled seroprevalence and prevalence of biopsy-confirmed Celiac disease (CeD) in the following 4 conditions: (i) cryptogenic cirrhosis, (ii) all-cause cirrhosis, (iii) cryptogenic hyper-transaminasemia, and (iv) all-cause hyper-transaminasemia. The results revealed a high seroprevalence (15.3%) and high prevalence of biopsy-confirmed CeD (4.6%) in patients with cryptogenic cirrhosis, a high seroprevalence of CeD in all-cause cirrhosis (14.2%), and a high seroprevalence (7.7%) and prevalence of biopsy-confirmed CeD (5.7%) in patients with cryptogenic hyper-transaminasemia. This systematic review confirms that patients with cryptogenic hyper-transaminasemia diagnosed with CeD show resolution of hyper-transaminasemia on a gluten-free diet (GFD), suggesting a reversal of liver injury. Even the patients with cryptogenic cirrhosis diagnosed with CeD also showed improved MELD and CTP scores, serum transaminases, and albumin within 6–24 months of a GFD. These observations suggest a potential causal relationship between CeD and liver disease, with a therapeutic role for a GFD in such patients. The results of this study suggest that nearly 1 in every 20 patients with cryptogenic cirrhosis or cryptogenic hyper-transaminasemia have CeD, which is approximately 5 times more common than in the general population. Hence, both of these groups should be considered high-risk populations for CeD screening. Physicians should be aware of the liver being a commonly involved extraintestinal organ in CeD to enable early detection and timely intervention. 

Archives of Pathology & Laboratory Medicine 

Cytomegalovirus Hepatitis in Allograft Livers may show Histologic Features of Acute Cellular Rejection 

Shih AR, Naini BV, Westerhoff M, et al. Arch Pathol Lab Med. 2023 Jun 1;147(6):655-664. 


Cytomegalovirus (CMV) hepatitis is an important infectious etiology to rule out in patients with allograft dysfunction in the early post-transplant period. Older literature relates the histologic overlap of CMV hepatitis with features of acute cellular rejection (ACR); however, immunosuppressive therapies have improved over the past 25 years and the authors sought to update these reports. They reviewed the histology from 26 patients who had undergone liver transplant with allograft biopsy in the years 2002-2009. Most patients had either a history of hepatitis C (38%) or alcoholic liver disease (23%). The average number of days from transplant to diagnosis of CMV hepatitis was 184 (11-747 days). Histologic review showed that 16 (62%) CMV hepatitis cases had clear “acute cellular rejection” features, including bile duct injury/loss, endotheliitis, and portal inflammation. These cases also had lobular inflammation, neutrophilic microabscesses, and sinusoidal lymphocytosis. The 10 (38%) cases without histologic features of ACR also had less lobular inflammation and fewer neutrophilic microabscesses. All cases had CMV-infected cells visible by H&E. All patients received antiviral therapy upon diagnosis, and increased immunosuppression was not necessary. The authors conclude that pathologists should be very conservative in their interpretation of acute cellular rejection in the setting of clear CMV hepatitis. 

Clinical Gastroenterology and Hepatology 

Correlation of LI-RADS 3 or 4 Observations with Histopathologic Diagnosis in Patients with Cirrhosis 

Dunn C, Lin B, Rich NE, et al. Clin Gastroenterol Hepatol. 2023 May;21(5):1351-1353.e2. 


This retrospective study correlated radiologic LI-RADS 3 and 4 observations (LR-3 and LR-4) with pathologic findings in explanted cirrhotic livers. Histologic review demonstrated hepatocellular carcinoma (HCC) in 65.6% of LR-4 lesions and 31% of LR-3 lesions. One patient with LR-3 observations was found to have angiosarcoma on explant. More than half with LR-3 and more than one-fourth with LR-4 observations had no pathologic correlate, suggesting these observations may be perfusion variants on imaging or regenerative cirrhotic nodules. While HCC in LR-3 and LR-4 lesions was associated with male gender, HCC risk was not associated with LR-3 or LR-4 maximum diameter. 


PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis 

Chen VL, Oliveri A, Miller MJ, et al. Gastroenterology. 2023;164(6):966-977.e17.  


The genetic mutations that may influence the rate of development of metabolic dysfunction-associated steatotic liver (MASLD; formerly nonalcoholic fatty liver disease, NAFLD) are explored in this study of ~54,000 participants from two independent cohorts, the Michigan Genomics Initiative (MGI) and UK Biobank (UKBB). The study finds that the PNPLA3-rs738409-GG genotype is associated with rapid progression to cirrhosis, particularly in patients with diabetes. The authors suggest that routine PNPLA3 genotyping in patients with diabetes and indeterminant fibrosis scores could identify a population at high risk of progression to cirrhosis. 

Refining Classification of Cholangiocarcinoma Subtypes via Proteogenomic Integration Reveals New Therapeutic Prospects 

Cho SY, Hwang H, Kim YH, et al. Gastroenterology. 2023 Jun;164(7):1293-1309.  


Intrahepatic cholangiocarcinoma has a poor prognosis with limited treatment options. In this study of 102 intrahepatic cholangiocarcinoma resection specimens, the authors performed extensive genomic, transcriptomic, proteomic, and phosphoproteomic analyses with the goal of identifying therapeutic targets. Several high-risk molecular subtypes were identified, which may inform the development of therapeutic agents. 


Mass cytometry-based peripheral blood analysis as a novel tool for early detection of solid tumours: a multicentre study 

Zhang Q, Ye M, Lin C, et al. Gut. 2023 May;72(5):996-1006.  


Mass cytometry time-of-flight (CyTOF) is a novel technology to profile the composition and number of immune cells, reflecting immunity in the higher-dimensional plane, which could be used in early tumor detection. These authors attempted to establish diagnostic models for hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) by performing CyTOF analysis for 2348 participants from 15 centers, including 1131 participants with hepatic diseases, 584 participants with pancreatic diseases and 633 healthy volunteers in this study. The authors determined the disturbance of systemic immunity caused by HCC and PDAC and calculated a peripheral blood immune score (PBIScore) based on the constructed model. The PBIScore exhibited good performance in detecting HCC and PDAC, with both sensitivity and specificity being around 80% in the validation cohorts. The authors further established an integrated PBIScore (iPBIScore) by combining PBIScore and alpha-fetoprotein or carbohydrate antigen 19-9. The authors claimed that the alterations of peripheral immune cell subsets could assist tumor detection, and provide a ready-to-use detection model for HCC and PDAC. 


Steatosis, HBV-related HCC, and HBsAg seroclearance: A systematic review and meta-analysis 

Mao X, Cheung KS, Peng C, et al. Hepatology 2023;77:1735-1745. 


Both NAFLD and chronic hepatitis B are causes of hepatocellular carcinoma. While it would seem intuitive that having both would accelerate the development of cirrhosis and HCC, the incremental impact of NAFLD on the development of HCC in patients with HBV remains controversial. In this meta-analysis, the authors analyze data from studies on patients with chronic HBV with or without radiologic or histologic steatosis (including MAFLD, steatosis, or NASH). Included studies were case-control, prospective or retrospective cohort studies, or randomized controlled trials that had as their study outcome HCC (diagnosed by imaging or histology), cirrhosis, advanced fibrosis, and HBsAg clearance. Thirty-four studies comprising 68,268 patients were included. Hepatic steatosis was found to significantly increase the risk of HCC in patients with chronic HBV (OR 1.59), particularly in studies with greater than 5 years of follow-up, histologic confirmation of steatosis, and high-quality studies. The incremental risk was largely abolished in patients on HBV therapy, presumably due to the reduced risk of HCC in HBV patients on nucleos(t)ide analogues. Not surprisingly, hepatic steatosis was also associated with the development of cirrhosis (OR 1.52), even after excluding patients with alcohol use.  Paradoxically, hepatic steatosis was significantly associated with higher HBsAg seroclearance (OR 2.22). The study confirms the contention that steatosis contributes to the development of cirrhosis and HCC in patients with chronic HBV infection. The mechanism whereby steatosis increases HBsAg clearance is not understood. 


Primary inflammatory myofibroblastic tumour of the liver: a clinicopathological and genetic study including a subset with ETV6::NTRK3 fusion 

Han Q, Zhang Z, He X, et al. Histopathology. 2023 May;82(6):925-936. 


Inflammatory myofibroblastic tumor (IMT) is an intermediate neoplasm and rarely occurs in the liver.  This article included 10 cases of primary IMT of the liver, including 4 males and 6 females, aged 1-48 years with a median age of 35. Three typical histological patterns were identified: hypercellular, hypocellular myxoid, and hypocellular fibrous.  Although cellularity and stroma varied, tumor cytology shared common features: relatively bland, plump to stellate cells with round or oval nuclei. By IHC, 6 of 10 cases were positive for ALK, and 3 of 4 ALK-negative cases were positive for pan-TRK. ETV6::NTRK3 fusion was confirmed by RT-PCR in the 3 pan-TRK-positive IMTs, but FISH-negative results were found in 2 of 3 cases. No genetic alteration or immunoreactivity for ALK/pan-TRK was detected in one tumor. 

Human Pathology 

Histologic features of allograft livers in patients treated for rejection before biopsy 

Leonard NB, Hale GL, Boylan KE, et al. Hum Pathol. 2023 May;135:11-21.: PMC10121875. 


Liver biopsy is often performed in liver transplant patients when clinical features are concerning for acute cellular rejection (ACR), and it has become more common for patients to receive treatment for presumed ACR prior to liver biopsy. However, the impact of pretreatment on the histopathologic triad of ACR (mixed portal inflammation, endothelialitis, and bile duct damage) is not well described. This study evaluated 70 liver transplant biopsies performed on 53 patients for suspected ACR between 2018 and 2021. ACR was diagnosed by histopathologic features in 37 tissue biopsies – among those cases, 17 received pretreatment with steroids, antithymocyte globulin, or increased immunosuppression prior to biopsy. The authors conclude that when evaluating biopsies for suspected ACR, the detection of bile duct inflammation/damage should raise the possibility of partially treated ACR, even in the absence of endothelialitis and portal inflammation. 

Liver pathology in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: vasculopathic disease beyond nodular regenerative hyperplasia.  

Khonde P, Chatterjee D, Bogacki M, et al. Hum Pathol. 2023 May;135:22-34.  


The authors of this autopsy study explore the hepatic features that occur in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), a rare autosomal dominant disease caused by a frame-shift mutation in TREX1. While it is known that the disease is associated with nodular regenerative hyperplasia, the full spectrum of histologic changes has not been explored. This study revealed a variety of additional pathologic changes in the liver, including other vascular abnormalities and heterogenous fibrous bands. 

Journal of Gastroenterology and Hepatology 

Immunostaining for hepatitis B viral antigens in liver: Association with clinical, biochemical, and virologic features of disease 

Kleiner DE, Lisker-Melman M, Wahed AS, et al. J Gastroenterol Hepatol. 2023 Jun;38(6):989-998. 


The authors evaluated 467 liver biopsies with chronic hepatitis B infection. Immunohistochemical stains for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) were performed and correlated with clinical parameters. HBsAg was positive in 90% of cases. HBsAg staining correlated with serum levels of HBsAg and hepatitis B viral DNA, but not with disease activity. HBcAg staining was positive in 49% of this cohort and correlated with the patient’s level of viremia and degree of liver injury. Overall, the authors concluded that immunostains for hepatitis B viral antigens yielded little clinical information that cannot be gained through less invasive serologic studies. 

Journal of Hepatology 

Acute severe non-A-E-hepatitis of unknown origin in children – A 30-year retrospective observational study from north-west Germany 

Leiskau C, Tsaka S, Meyer-Ruhnke L, et al. J Hepatol. 2023 May;78(5):971-978. 


In this study, the authors present an observational study of cases of severe acute non-A-E-hepatitis (NAEH) in pediatric patients in North-West Germany over 30 years, comparing a historic cohort (79 cases; 1990-2018) to a COVID-19 era (“current”) cohort (28 cases; 2019-2022), with the aim of describing the incidence and outcomes of severe NAEH. 107 patients were included in the study. The annual incidence rose from 2.2 (historic cohort) to 4.25/center/year, but the historic cohort consisted of more severe cases, with a higher proportion of patients requiring ICU treatment and liver transplantation, and higher mortality. 57 patients had clinical signs of infection, with most common proven potential pathogens at diagnosis including HHV-6 (4), CMV (3), HSV (3), EBV (3), and enterovirus (2); adenovirus DNA was detected in two patients (one patient who developed acute liver failure after symptoms of gastroenteritis, with concomitant detection of EBV, recovered without transplant; one patient who developed acute liver failure after respiratory tract infection, with adenovirus detected in stool, transplanted). 25 patients developed hepatitis-associated aplastic anemia (HAAA), 5 of whom died during follow-up. 69 patients met the criteria of pediatric acute liver failure and 44 underwent liver transplantation. Factors associated with increased transplant-free survival included proven infection, especially when associated with gastrointestinal symptoms, and higher ALT at diagnosis. Factors associated with decreased transplant-free survival included jaundice/higher bilirubin levels, higher INR at diagnosis, and hepatic encephalopathy. Patients in the current cohort also had better outcomes than those in the historic cohort. Overall, the incidence of NAEH has increased in this study in the current cohort, but without a clear link to adenovirus infection, as reported in other countries, including the United Kingdom. Further prospective studies are needed to determine the pathophysiology of NAEH and the role of isolation for subsequent viral infections in non-immune children. 

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 

Joseph Misdraji, MD; Yale School of Medicine 

Meredith Pittman, MD; Maimonides Medical Center 

Daniel Roberts, MD; Cleveland Clinic 

Xuefeng Zhang, MD; Cleveland Clinic  

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