Hepatology consultation is associated with decreased early return to alcohol use after discharge from an inpatient alcohol use disorder treatment program.

BACKGROUND: Alcohol cessation is the only intervention that both prevents and halts the progressions of alcohol-associated liver disease. The aim of this study was to assess the relationship between a return to alcohol use and consultation with hepatology in treatment-seeking patients with alcohol use disorder (AUD). METHODS: Two hundred forty-two patients with AUD were enrolled in an inpatient treatment program, with hepatology consultation provided for 143 (59%) patients at the request of the primary team. Patients not seen by hepatology served as controls. The primary outcome was any alcohol use after discharge assessed using AUDIT-C at 26 weeks after discharge. RESULTS: For the primary endpoint, AUDIT at week 26, 61% of the hepatology group and 28% of the controls completed the questionnaire (p=0.07). For the secondary endpoint at week 52, these numbers were 22% and 11% (p = 0.6). At week 26, 39 (45%) patients in the hepatology group versus 31 (70%) controls (p = 0.006) returned to alcohol use. Patients evaluated by hepatology had decreased rates of hazardous alcohol use compared to controls, with 36 (41%) versus 29 (66%) (p = 0.008) of the patients, respectively, reporting hazardous use. There were no significant differences in baseline characteristics between groups and no difference in rates of prescribing AUD therapy. There was no difference in outcomes at 52 weeks. CONCLUSIONS: Patients evaluated by hepatology had significantly lower rates of return to alcohol use and lower rates of hazardous drinking at 26 weeks but not at 52 weeks. These findings suggest that hepatology evaluation during inpatient treatment of AUD may lead to decreased rates of early return to alcohol use.

Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders.

BACKGROUND AND AIMS: Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are characterized by very short telomeres and multisystem organ involvement including liver disease. Our study aimed to characterize baseline hepatic abnormalities in patients with DC/TBD and determine risk factors associated with liver disease progression. APPROACH AND RESULTS: A retrospective review was performed on a cohort of 58 patients (39 males) with DC/TBD who were prospectively evaluated at a single institute from 2002 to 2019. The median age at initial assessment was 18 (1.4-67.6) years, and median follow-up duration was 6 (1.4-8.2) years. Patients with autosomal or X-linked recessive inheritance and those with heterozygous TINF2 DC were significantly younger, predominantly male, and more likely to have DC-associated mucocutaneous triad features and severe bone marrow failure compared with autosomal dominant-non- TINF2 DC/TBD patients. Liver abnormality (defined at baseline assessment by laboratory and/or radiological findings) was present in 72.4% of patients with predominantly cholestatic pattern of liver enzyme elevation. Clinically significant liver disease and portal hypertension developed in 17.2% of patients during the 6-year follow-up; this progression was mainly seen in patients with recessive or TINF2 -associated DC. Significant risk factors associated with progression included the presence of pulmonary or vascular disease. CONCLUSIONS: Our experience shows a high prevalence of cholestatic pattern of liver abnormality with progression to portal hypertension in patients with DC/TBD. Presence of pulmonary and/or vascular disease in patients with recessive or TINF2 DC was an important predictor of liver disease progression, suggesting the need for increased vigilance and monitoring for complications in these patients.

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.

Lipoprotein Insulin Resistance Index Reflects Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease.

The recently developed lipoprotein insulin resistance index (LP-IR) incorporates lipoprotein particle numbers and sizes and is considered to reflect both hepatic and peripheral IR. As tissue IR is a strong component of nonalcoholic fatty liver disease (NAFLD) pathogenesis, we aimed to assess the degree by which LP-IR associates with hepatic fat content. This was a single-center retrospective analysis of patients with NAFLD. LP-IR, the homeostasis model assessment of insulin resistance (HOMA-IR), and adipose tissue IR (Adipo-IR) were measured simultaneously. Liver fat content was estimated by FibroScan controlled attenuated parameter. Associations were assessed using Spearman's correlation and multivariate linear regression. The study included 61 patients. LP-IR was correlated with HOMA-IR (ρ = 0.30; P = 0.02), typically thought to reflect hepatic IR, but not with Adipo-IR (ρ = 0.15; P = 0.25). Liver fat content was significantly associated with Adipo-IR (ρ = 0.48; P < 0.001), LP-IR (ρ = 0.35; P = 0.005), and to a lesser degree with HOMA-IR (ρ = 0.25; P = 0.051). The association of liver fat with LP-IR was limited to patients without diabetes (ρ = 0.60; P < 0.0001), whereas no association was seen in those with diabetes. In a multivariate model, Adipo-IR, LP-IR, and diabetes were independently associated with liver fat and together explained 35% of the variability in liver fat. Conclusion: LP-IR is a reasonable measure of IR in non-diabetic patients with NAFLD and is associated with hepatic fat content. Although adipose tissue is the major contributor to liver fat, the additional contribution of nonadipose tissues can be easily estimated using LP-IR.

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.

Stimulating More Than Just the Granulocytes: Drug-Induced Liver Injury From Filgrastim.

Granulocyte-colony-stimulating factors such as filgrastim are currently used for multiple indications, one of which is administration to healthy donors for allogeneic stem cell collection. So far, filgrastim has not been described as a cause of drug-induced liver injury. We report a case of drug-induced liver injury secondary to filgrastim use in a 54-year-old healthy donor. The patient presented with an upsurge of liver enzymes a week from the drug administration with a rapid downtrend over the next few weeks. We wish to highlight the possibility of a similar idiosyncratic adverse drug reaction in other healthy individuals.

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.

Twitter As a Noninvasive Bio-Marker for Trends in Liver Disease.

With the success of hepatitis C virus (HCV) direct-acting antiviral therapies, there has been a shift in research focus to the other major chronic liver diseases (CLDs). The use of social media, specifically Twitter, has become a popular platform for understanding public health trends and for performing health care research. To evaluate this, we studied the areas of public interest and social media trends of the following three major CLDs: hepatitis B virus (HBV), HCV, and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). Twitter activity data from January 1, 2013, through January 1, 2019, for HBV, HCV, and NAFLD/NASH were collected using the social media analytic tool Symplur Signals (Symplur LLC) software. Content and regression analyses were performed to understand and predict Twitter activity for each of the CLDs. Over the study period, there were 810,980 tweets generating 4,452,939,516 impressions. HCV tweet activity peaked in 2015 at 243,261 tweets, followed by a decline of 52.4% from 2015 to 2016 with a subsequent plateau through 2018. Meanwhile, NAFLD/NASH and HBV tweet activity has continued to increase, with projections that these two CLDs will surpass HCV by the second half of 2023 and 2024, respectively. Treatment and Management was the most popular content category for HCV and NAFLD/NASH, while Prevention was the most popular content category for HBV. Conclusion: Twitter is a useful social media tool to gauge public interest in liver disease over time. The information provided by Twitter can be used to identify gaps in public knowledge or highlight areas of interest that may need further research. Future studies on the use of Twitter in liver disease are warranted.

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.

PNPLA3 gene predicts clinical recovery after sustained virological response in decompensated hepatitis C cirrhosis.

BACKGROUND: Patients with decompensated hepatitis C virus (HCV) cirrhosis experience various outcomes after sustained virological response (SVR), ranging from clinical recovery to further deterioration. We hypothesised that the genetic risk for steatosis, namely the polymorphisms rs738409 of Patatin-like Phospholipase Domain-Containing 3 (PNPLA3), rs58542926 of Transmembrane-6-Superfamily-2 (TM6SF2), and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 (MBOAT7), is predictive of recovery. METHODS: We prospectively enrolled 56 patients with Child-Pugh (CPT) B/C cirrhosis who underwent antiviral therapy. The primary outcome was change in CPT score at 12, 24, and 48 weeks after SVR. We used a linear mixed-effects model for analysis. RESULTS: Forty-five patients (PNPLA3: 21 CC, 19 CG, 5 GG) survived to the first endpoint without liver transplantation. The mean change in CPT score at 12, 24, and 48 weeks was -1.57 (SE=0.30), -1.76 (SE=0.32), and -2.0 (SE=0.36), respectively, among the patients with the PNPLA3 CC genotype and -0.50 (SE=0.20), -0.41 (SE=0.25), and -0.24 (SE=0.27), respectively, among the other 24 patients. After adjustment for baseline characteristics, the PNPLA3 CG/GG genotypes were associated with a 1.29 (SE=0.30, p<0.0001) point higher CPT score. Most of the difference came from differences in hepatic encephalopathy and bilirubin. The results for rs58542926 and rs641738 were not significant. CONCLUSION: The PNPLA3 CG/GG genotypes could identify a subgroup of patients with decompensated HCV cirrhosis that had suboptimal clinical recovery despite SVR. An understanding of the genetic factors that influence clinical outcomes will help target patients for liver transplant based on individual genetic risk factors and provide insight leading to new therapeutic approaches.

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.