Development of hepatic fibrosis in common variable immunodeficiency-related porto-sinusoidal vascular disorder.

BACKGROUND AND AIMS: Liver involvement is an increasingly recognised complication of common variable immunodeficiency (CVID). Nodular regenerative hyperplasia (NRH), a subgroup of porto-sinusoidal vascular disorder, and manifestations of portal hypertension (PH) unrelated to cirrhosis are the most common findings. Nonetheless, the evolution of liver disease over time remains unknown. METHODS: Retrospective review of patients followed at the National Institutes of Health with CVID-related liver disease and liver biopsy from 1990 to 2020. Clinical, imaging and histological follow-up were recorded as part of clinical research protocols. RESULTS: Forty patients were included, with a median age of 37.5 years at initial biopsy, 73% presenting with clear evidence of NRH, and a median fibrosis stage of 1. At biopsy, median platelet count was 100 × 109/L, spleen size 19.5 cm, hepatic venous pressure gradient 9.5 mmHg and 37.5% of patients had signs of PH. Cumulative incidence of PH was 65% at 5 years. In a subgroup of 16 patients, a follow-up liver biopsy, performed at a median time of 3 years after the index biopsy, revealed an increase in fibrosis by ≥2 stages in 31% of cases and an increase to an overall stage of 2.2 (p = 0.001). No clinical or histological factors were associated with progression of fibrosis. CONCLUSIONS: In this CVID cohort, NRH is the most common initial histological finding; however, unexpectedly fibrosis progresses over time in a subgroup of patients. A better understanding of the underlying causal process of liver disease CVID might lead to improved outcomes.

Severe combined immunodeficiency: improved survival leading to detection of underlying liver disease.

BACKGROUND: Adenosine deaminase deficiency (ADA) is an autosomal recessive disorder leading to severe combined immunodeficiency (SCID). It is characterized patho-physiologically by intracellular accumulation of toxic products affecting lymphocytes. Other organ systems are known to be affected causing non-immune abnormalities. We aimed to conduct a cross sectional study to describe liver disease in autosomal recessive ADA-SCID. METHODS: Single center retrospective analysis of genetically confirmed autosomal recessive ADA-SCID was performed. Liver disease was defined as ≥1.5x the gender specific upper limit of normal (ULN; 33 IU/L for males and 25 IU/L for females) alanine aminotransferase (ALT) or moderate and severe increase in liver echogenicity on ultrasound. RESULTS: The cohort included 18 patients with 11 males. The median age was 11.5 (3.5-30.0 years) and median BMI percentile was 75.5 [36.75, 89.5]. All patients received enzyme replacement therapy at the time of evaluation. Seven (38%) and five (27%) patients had gene therapy (GT) and hematopoietic stem cell transplant (HSCT) in the past. Five patients had 1.5x ALT level more than 1.5x the U. Liver echogenicity was mild in 6 (33%), moderate in 2 (11%) and severe in 2 (11%) patients. All patients had normal Fibrosis-4 Index and Non-alcoholic fatty liver disease fibrosis biomarker scores indicating absence of advanced fibrosis in our cohort. Of 5 patients who had liver biopsies, steatohepatitis was noted in 3 patients (NAS score of 3,3,4). DISCUSSION: Non-immunologic manifestations of ADA-SCID have become more apparent in recent years as survival improved. We concluded that steatosis is the most common finding noted in our ADA-SCID cohort.

Clinical Vignettes Part I.

Patients with sickle cell disease and/or (rarely) trait are at increased risk for developing recurrent episodes of priapism, also known as stuttering priapism, and major ischemic priapism. Treatment of acute ischemic priapism is reactive; whereas ideal management consists of preventative approaches to ultimately promote the best improvement in patient's quality of life. Leg ulcers in patients with sickle cell disease (SCD) are quite common, with ∼20 % of patients with HBSS reporting either having an active or a past ucler. They can be confused with venous ulcers, with lower extremity hyperpigmentation confounding further the diagnosis. Several factors believed to contribute to the development of leg ulcers in patients with SCD are discussed in this article. Sickle cell liver disease (SCLD) occurs because of a wide variety of insults to the liver that happen during the lifetime of these patients. SCLD includes a range of complications of the hepatobiliary system and is increasing in prevalence with the aging adult sickle population. Liver nodular regenerative hyperplasia (NRH) is more common than realized and underappreciated as a diagnosis and requires liver biopsy with reticulin staining. Undiagnosed, the insidious damage from liver NRH can lead to noncirrhotic portal hypertension or cirrhosis.

Nodular Regenerative Hyperplasia of the liver in Juvenile Dermatomyositis.

BACKGROUND: We present two cases of Nodular Regenerative Hyperplasia (NRH) associated with Juvenile Dermatomyositis (JDM). CASE PRESENTATION: Case 1: A nine-year-old Caucasian male with refractory JDM and anti-NXP2 autoantibodies was diagnosed at age two. Over seven years, he developed arthritis, dysphagia, dysphonia, severe calcinosis, and colitis. Complications included recurrent cellulitis, infections, and hepatosplenomegaly. Multiple medications were chronically used, including prednisone, methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, rituximab, tacrolimus, etanercept, abatacept, infliximab, and tocilizumab. Case 2: A 19-year-old Asian female with chronically active JDM and anti-MDA5 autoantibodies was diagnosed at age 15. Symptomatology included ulcerative skin lesions, Raynaud's phenomenon with digital ulcers, arthritis, interstitial lung disease with pulmonary hypertension, and calcinosis. Medications included chronic use of prednisone, methotrexate, abatacept, cyclophosphamide, mycophenolate mofetil, rituximab, tofacitinib, and sildenafil. In both patients, clinical symptomatology was not suggestive of liver disease or portal hypertension, but laboratory studies revealed elevated serum transaminases with progressive thrombocytopenia and no active liver-associated infections. The first patient's liver ultrasound showed coarse hepatic texture with mild echogenicity, splenomegaly, and portal hypertension. The second patient's liver ultrasound was normal, but elastography indicated increased stiffness. Liver biopsy confirmed NRH in both patients. CONCLUSIONS: It is difficult to recognize NRH in JDM, as it often presents with elevated transaminases which may be mistaken for JDM muscle flare, corticosteroid-related fatty liver, or medication-related transaminitis. NRH has been associated with several medications used to treat JDM, including methotrexate, azathioprine, and cyclophosphamide, which should be discontinued if NRH develops. Providers should consider NRH in JDM patients with severe, refractory disease who have persistently elevated transaminases and persistent thrombocytopenia.

Systematic review with meta-analysis: the impact of functional cure on clinical outcomes in patients with chronic hepatitis B.

BACKGROUND: Although hepatitis B surface antigen (HBsAg) loss is considered the ideal therapeutic endpoint for the treatment of chronic hepatitis B virus (HBV) infection, its impact on clinical outcomes remains uncertain. AIM: To assess the impact of HBsAg loss on clinical outcomes following spontaneous and treatment-related HBsAg loss. METHODS: We searched PUBMED, Embase, the Cochrane library, and published abstracts through to May 2021 for studies that reported HBsAg loss, had >1 year of follow-up and reported at least one clinical outcome in adults with chronic HBV infection. RESULTS: We identified 57 studies (258 744 HBsAg-positive patients, 63 270 with HBsAg loss). Based on 24 studies including 160 598 patients with and without HBsAg loss, HBsAg loss was associated with a non-significant 23% relative risk reduction of developing hepatocellular carcinoma (HCC) compared to those who remained HBsAg-positive (RR = 0.77; 95% CI: 0.38-1.57). In subgroup meta-analysis of 10 studies, treatment-related HBsAg loss was associated with a non-significant higher pooled proportion of HCC (0.94%) compared to spontaneous HBsAg loss (0.45%). HCC development after HBsAg loss was significantly higher in males, those with underlying cirrhosis, and those with a family history of HCC. HBsAg loss was associated with lower pooled proportions of incident cirrhosis, hepatic decompensation, overall and liver-related mortality compared to no HBsAg loss. Substantial heterogeneity was noted across studies for all outcomes. CONCLUSION: HBsAg loss is associated with a reduced risk of clinical outcomes. However, several shortcomings in the published studies prevent a more definitive conclusion on the potential benefits of HBsAg loss.

The Natural History of Pancreatic Cystic Lesions in Liver Transplant Recipients: A Systematic Review and Meta-analysis.

OBJECTIVES: The management of incidentally discovered pancreatic cystic lesions (PCLs) with surveillance or resection often requires shared decision-making. Patients with cirrhosis are more likely to have PCLs discovered due to increased imaging, and those undergoing liver transplantations (LTs) may be at increased risk of carcinogenesis due to immunosuppressive medications. Our study aimed to characterize the outcomes and risk of malignant progression of PCLs in post-LT patients. METHODS: Multiple databases were searched for studies looking at PCLs in post-LT patients from inception until February 2022. Primary outcomes were the incidence of PCLs in LT recipients and progression to malignancy. Secondary outcomes included development of worrisome features, outcomes of surgical resection for progression, and change in size. RESULTS: A total of 12 studies with 17,862 patients with 1411 PCLs were included. The pooled proportion of new PCL development in post-LT patients was 68% (95% confidence interval [CI], 42-86; I2 = 94%) over the follow-up of 3.7 (standard deviation, 1.5) years. The pooled progression of malignancy and worrisome features was 1% (95% CI, 0-2; I2 = 0%) and 4% (95% CI, 1-11; I2 = 89%), respectively. CONCLUSIONS: Compared with nontransplant patients, incidental PCLs do not carry a higher risk of malignancy.

CHEK2 mutation in a patient with pancreatic adenocarcinoma-a rare case report.

Pancreatic cancer (PaCa) is very aggressive malignancy with poor prognosis. Individuals with a family history of PaCa have a higher risk of developing cancer which points to a hereditary component. Here, we report a unique case of CHEK2 mutant PaCa in a patient with no medical but significant family history. A 59-year old female presented with 3-month history of worsening epigastric pain and jaundice. CT abdomen/pelvis with contrast showed pancreatic head mass which was confirmed by endoscopic ultrasound guided biopsy. She was diagnosed with pancreatic adenocarcinoma harboring CHEK2 mutation. She had extensive surgery followed by adjuvant chemotherapy. Follow up imaging in 3 months obtained after surgery and adjuvant chemotherapy showed extensive liver metastasis and patient decided to pursue hospice. Germline testing in all PaCa patients has become essential as mutations in CHEK2 and other DNA repair genes constitute a unique subset of PaCas. Not only does it help in assessment of cancer risk in the individual and family members but also guide anticancer therapy selection. PaCa patients harboring CHEK2 mutations do not usually respond to chemotherapeutic agents such as gemcitabine. However, new treatment strategies such as PARP inhibitors targeting defective DNA repair mechanism are currently being investigated and showed some promise in treating CHEK2 mutant PaCa patients.

Rare case of triple mutant (KRAS + NRAS + BRAF) metastatic colon adenocarcinoma.

KRAS is detected in 30%-50% of colorectal cancer (CRC) and BRAF mutations are found in 10% of CRC. A 62-year-old man with the long-standing smoking history presented to the emergency department with abdominal pain, weight loss and constipation. CT scan of abdomen/pelvis showed obstructive mass which was found to be colon adenocarcinoma which on further molecular analysis tested positive for KRAS, NRAS and BRAF mutations. His tumour progressed despite chemotherapy and surgery and he died within a year of diagnosis. Concomitant KRAS, NRAS and BRAF mutations are rare enough to be considered mutually exclusive but coexistent mutations appear to be a distinct molecular and clinical subset which needs new and effective treatment strategies in a setting of dismal prognosis.

WHO Guidelines for Prevention, Care and Treatment of Individuals Infected with HBV: A US Perspective.

The prevalence of chronic hepatitis B (CHB) differs globally. CHB is responsible for 30% of all deaths from cirrhosis and 40% from hepatocellular carcinoma. The WHO developed guidelines in 2015 on prevention, care, and treatment of chronic HBV infection targeted to program managers in all health care settings, particularly in low- and middle-income countries. Several of the recommendations differ from those of the major Liver Societies, including the American Association for the Study of Liver Diseases (AASLD). This review highlights key differences between the AASLD and WHO guidelines and discusses the impact on management of CHB.

SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway.

BACKGROUND: Optimal therapeutic strategies for hepatocellular carcinoma (HCC) patients are still challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Growing evidence shows that genetic and epigenetic alterations are involved in HCC progression and resistance to therapy, however the molecular mechanisms underlying resistance to therapy have not been fully understood. METHODS: Expression of SIRT7 in 17 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry and Western blot. The mRNA expression of SIRT7 in 20 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by quantitative RT-PCR. The biologic consequences of overexpression and knockdown of SIRT7 in HCC therapy sensitivity were studied in vitro and in vivo. Interaction between SIRT7 and p53 were studied in HCC cell lines. RESULTS: SIRT7 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with TACE-resistance and poor survival (P = 0.008.) Depletion of SIRT7 from multiple liver cancer cell lines significantly increased doxorubicin toxicity while overexpression of SIRT7 largely abolished doxorubicin induced apoptosis. At the molecular level, we observed that SIRT7 interacts with and induces deacetylation of p53 at lysines 320 and 373. Deacetylated p53 showed significantly less affinity for the NOXA promoter and its transcription. In mouse xenografts, SIRT7 suppression increased doxorubicin induced p53 activation, inhibited tumor growth and induced apoptosis. CONCLUSION: The newly identified SIRT7-p53-NOXA axis partially illustrates the molecular mechanism of HCC resistance to therapy and represents a novel potential therapeutic target for HCC treatment.

Estimating neoplasia detection rate (NDR) in patients with Barrett's oesophagus based on index endoscopy: a systematic review and meta-analysis.

BACKGROUND: Biopsies are obtained to confirm intestinal metaplasia and rule out prevalent dysplasia and cancer when Barrett's oesophagus (BE) is detected at index upper endoscopy (oesophagogastroduodenoscopy [EGD]). AIM: The purpose of this systematic review was to obtain summary estimates of the prevalence of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (EAC) associated with BE during index EGD for chronic GERD symptoms, defined as neoplasia detection rate (NDR) which could be used as a quality measure. METHODS: An extensive search was performed within PUBMED, EMBASE and the Cochrane Library databases to identify studies in which patients underwent index endoscopy for the evaluation of the presence of BE. Two reviewers independently evaluated both the study eligibility and methodological quality and data extraction. A random-effects model (REM) based on the binomial distribution was used to calculate the pooled effects of the prevalence of BE-associated dysplasia and EAC. RESULTS: For the calculation of dysplasia and EAC prevalence rates, a total of 11 studies with 10 632 patients met the inclusion criteria including 80.4% men with a mean age of 58.7 years and average BE length of 3.5 cm. The pooled prevalence of EAC, HGD and LGD was 3%(95% CI 2 to 5, 9 studies: 396/10 539 patients), 3%(95% CI 2 to 5 [REM], 9 studies: 388/10 539 patients) and 10%(95% CI 7 to 15 [REM], 10 studies: 907/8945 patients), respectively. For NDR, that is, the pooled prevalence of HGD/EAC was 7%(95% CI 4 to 10 [REM], 10 studies: 795/10 632 patients). CONCLUSION: NDR is approximately 4% and could be used as a quality measure.

PRMT1-Dependent Macrophage IL-6 Production Is Required for Alcohol-Induced HCC Progression.

Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms are not well understood. Several studies suggested that alcohol promotes tumor growth by altering immune cell phenotypes in the liver. Arginine methylation is a common posttranslational modification generated mostly by a single protein, PRMT1. In myeloid cells PRMT1 is a key regulator of immune response. Myeloid-specific PRMT1 knockout mice are hyperresponsive to LPS and deficient in PPARγ-dependent macrophage M2 polarization. We aimed to define the role of myeloid PRMT1 in alcohol-associated liver tumor progression using a mouse model of DEN injection followed by Lieber-DeCarli alcohol liquid diet feeding. We found that PRMT1 knockout mice showed significantly lower expression of IL-10 and IL-6 cytokines in the liver and downstream STAT3 activation, which correlated with reduced number of surface tumors, reduced proliferation, and reduced number of M2 macrophages in the liver as well as within proliferating nodules. We found that blocking IL-6 signaling in alcohol-fed mice reduced the number of tumors and liver proliferation in wild-type mice but not in knockout mice suggesting that reduced IL-6 in PRMT1 knockout mice contributes to the protection from alcohol. Additionally, PRMT1 knockout did not show any protection in tumor formation in the absence of alcohol. Finally, we confirmed that this mechanism is relevant in humans. We found that PRMT1 expression in tumor-associated macrophages correlated with STAT3 activation in human HCC specimens. Taken together, these data suggest that the PRMT1-IL-6-STAT3 axis is an important mechanism of alcohol-associated tumor progression.

Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice.

Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain-containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte-specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol-fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P < 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients. CONCLUSION: Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (Hepatology 2018;67:1109-1126).

Are All Mutations the Same? A Rare Case Report of Coexisting Mutually Exclusive KRAS and BRAF Mutations in a Patient with Metastatic Colon Adenocarcinoma.

29-year-old Hispanic woman presented to the clinic with complaints of abdominal pain, nausea, fatigue, and constipation. Laboratory tests indicated the presence of iron deficiency anemia and transaminitis. Imaging evaluation revealed marked hepatomegaly with multiple hepatic metastases and pelvic lymphadenopathy. Biopsy of the hepatic lesions showed adenocarcinoma positive for pan-cytokeratin, CMA5.2, villin, and CDX2. She was positive for tumor markers CA 19-9, CA-125, and CEA. Upon further evaluation, she was found to have colorectal cancer positive for KRAS and BRAF mutations. Unfortunately, her disease progressed rapidly and she expired within 3 months from the time of her first diagnosis. KRAS and BRAF mutations are rare enough to be considered virtually mutually exclusive but coexistent mutations appear to be a distinct molecular and clinical subset with aggressive course of illness, which is in dire need of new treatment strategies. Panitumumab and Cetuximab are approved for patients with wild type KRAS CRC. Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF and its use in BRAF mutated colon cancer remains to be well established. Our report highlights the need to obtain tissue samples from these patients for analysis and to evaluate the benefit of Vemurafenib in colorectal cancers.