Primary Non-HFE Hemochromatosis: A Review.

Iron homeostasis is a complex process in which iron uptake and use are tightly balanced. Primary Type 1 or HFE hemochromatosis results from homozygous mutations in the gene that encodes human homeostatic iron regulator (known as human factors engineering, HFE) protein, a regulator of hepcidin, and makes up approximately 90% of all hemochromatosis cases. However, four types of hemochromatosis do not involve the HFE gene. They are non-HFE hemochromatosis type 2A (HFE2, encoding HJV), type 2B (HAMP, encoding hepcidin), type 3 (TFR2, encoding transferring receptor-2), and types 4A and B (SLC40A1, encoding ferroportin. Non-HFE hemochromatosis is extremely rare. Pathogenic allele frequencies have been estimated to be 74/100,000 for type 2A, 20/100,000 for type 2B, 30/100,000 for type 3, and 90/100,000 for type 4 hemochromatosis. Current guidelines recommend that the diagnosis be made by ruling out HFE mutations, history, physical examination, laboratory values (ferritin and transferrin saturation), magnetic resonance or other imaging, and liver biopsy if needed. While less common, non-HFE hemochromatosis can cause iron overload as severe as the HFE type. In most cases, treatment involves phlebotomy and is successful if started before irreversible damage occurs. Early diagnosis and treatment are important because it prevents chronic liver disease. This review updates the mutations and their pathogenetic consequences, the clinical picture, diagnostic guidelines, and treatment of hemochromatosis.

The Supportive Role of Provocative Maneuvers and Impedance Clearance in Detecting Ineffective Esophageal Motility.

Background: Ineffective esophageal motility (IEM) is one of the most common esophageal motility disorders. However, the definition of IEM has evolved. Chicago classification version 4.0 (CCv4.0) made IEM parameters more stringent with greater than 70% of ineffective wet swallows (WS) necessary to diagnose conclusive IEM. Of the ineffective swallows, 50-70% are deemed "inconclusive cases". This study sought to determine whether provocative maneuvers, including multiple rapid swallows (MRS) and apple viscous swallows (AVS), and impedance clearance can provide supportive information for inconclusive IEM disorders based on CCv4.0. Methods: Esophageal motility data on 100 patients were analyzed. All patients completed WS and at least one additional swallow test (MRS and/or AVS). Patients were classified as having conclusive IEM, inconclusive IEM, or normal motility. IEM features detected on MRS/AVS and incomplete bolus clearance were recorded. Percentage of agreement between IEM features and incomplete bolus clearance was calculated for each motility group. Results: Ten patients had conclusive IEM, nine had inconclusive IEM, and 32 had normal motility. There was 70% agreement between IEM features and incomplete bolus clearance with conclusive IEM, 33% agreement with inconclusive IEM, and 9% agreement with normal motility. There was significantly more agreement in the conclusive and inconclusive IEM groups than in the normal motility group (P = 0.0003). Conclusions: Combinational follow-up testing with provocative maneuvers and impedance clearance may assist with risk stratification of IEM patients and assist in further management of inconclusive IEM. MRS and AVS can detect unique IEM features that may help with preoperative management of inconclusive IEM.

Cautious optimism in anticipation of hepatitis B curative therapies.

Despite relative effectiveness of current hepatitis B therapies, there is still no curative agents available. The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen. Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection, which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.

Rebuilding trust in proton pump inhibitor therapy.

Introduction of proton pump inhibitor (PPI) therapy into clinical practice has revolutionized treatment approach to acid-related diseases. With its clinical success came a widespread use of PPI therapy. Subsequently, several studies found that PPIs were oftentimes overprescribed in primary care and emergency setting, likely attributed to seemingly low side-effect profile and physicians having low threshold to initiate therapy. However, now there is a growing concern over PPI side-effect profile among both patients and providers. We would like to bring more awareness to the currently available guidelines on PPI use, discuss clinical indications for PPIs and the evidence behind the reported side-effects. We hope that increased awareness of proper PPI use will make the initiation or continuation of therapy a well informed and an evidence-based decision between patient and physician. We also hope that discussing evidence behind the reported side-effect profile will help clarify the growing concerns over PPI therapy.

Statin-induced Liver Injury Patterns: A Clinical Review.

Since their introduction in 1987, hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, more commonly known as statins, have become some of the most widely prescribed medications in the world. Though generally considered to be safe and well tolerated, statins have been associated with several side effects including mild liver dysfunction manifested by increases in aminotransferases. Rarely, statins have been noted to induce more serious hepatic injury, including liver injury with autoimmune features. Current literature supports statin induced liver injury presenting in either hepatocellular or cholestatic patterns, though with the former being the prevailing pattern of injury. Fortunately, severe liver injury is uncommon with statin use and is generally reversible without any intervention other than offending statin cessation. When evaluating cases of suspected statin-induced liver injury, a complete medical history, laboratory tests including a complete metabolic panel, autoimmune markers, and viral panel, as well as hepatic imaging, are crucial for a complete causality analysis with validated tools such as Roussel Uclaf Causality Assessment Method. The aim of this review is to review the current evidence for statin-induced liver injury and cholestasis.

Lessons learned: Preventable misses and near-misses of endoscopic procedures.

Endoscopy is a complex procedure that requires advanced training and a highly skilled practitioner. The advances in the field of endoscopy have made it an invaluable diagnostic tool, but the procedure remains provider dependent. The quality of endoscopy may vary from provider to provider and, as a result, is not perfect. Consequently, 11.3% of upper gastrointestinal neoplasms are missed on the initial upper endoscopy and 2.1%-5.9% of colorectal polyps or cancers are missed on colonoscopy. Pathology is overlooked if endoscopic exam is not done carefully, bypassing proper visualization of the scope's entry and exit points or, if exam is not taken to completion, not visualizing the most distal bowel segments. We hope to shed light on this issue, establish areas of weakness, and propose possible solutions and preventative measures.

Could microbiome analysis be a new diagnostic tool in gastric carcinogenesis for high risk, Helicobacter pylori negative patients?

Helicobacter pylori (H. pylori) has long been believed to be the major colonizer of the stomach, but recent advances in genetic sequencing have allowed for further differentiation of the gastric microbiome and revealed the true complexity of the gastric microbiome. One of the few studies specifically evaluated the microbiome in the H. pylori negative patient population. They concluded that various stages of gastric carcinogenesis are associated with distinct bacterial taxa that could service both a predictive and diagnostic purpose. While the study has some limitations, the conclusions they make are intriguing and should prompt a larger prospective study to be done that spans multiple geographic regions.

The Unusual Suspect: An Acute Gastric Dilation With Volvulus in a Scleroderma Patient.

Systemic scleroderma (SSc) is a chronic autoimmune disorder that can affect various organ systems. About 90% of patients with SSc have gastrointestinal (GI) manifestations, with esophageal dysmotility being the most frequently reported. While esophageal involvement is the most common, other segments of the upper GI tract can be affected as well, such as the stomach or small bowel. Some of the examples of gastric involvement include gastric antral vascular ectasia (GAVE) and gastroparesis. Small bowel involvement can present with reduced contractility, pseudo-obstruction, small intestinal bacterial overgrowth (SIBO), and atrophy. Although many of these manifestations bear little clinical urgency, acute gastric dilation or pseudo-obstruction constitute a medical emergency and require prompt intervention. We are presenting a case of acute gastric dilation with gastric volvulus in the setting of SSc, which is not well reported in the medical literature. We hope to increase providers' awareness of this rare manifestation of SSc to facilitate prompt diagnosis and intervention. Furthermore, we hope to prompt more research to be done to better understand its pathophysiology and determine whether this manifestation of SSc is preventable.

Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.

Hidden in Plain Sight: Esophageal Dysmotility in Patients With Systemic Lupus Erythematosus.

Among the patients who present to the emergency room or a primary care office with symptoms of dysphagia, chest pain, and reflux, approximately 9% have an underlying rheumatological condition. It is not surprising that many emergency and internal medicine clinicians frequently overlook this etiology and investigate other causes first. However, an overwhelming number of patients with rheumatological conditions (61.1%) have some form of esophageal dysmotility that ranges from ineffective esophageal motility (IEM) to achalasia. We present a case of systemic lupus erythematosus (SLE) with absent contractility that was initially overlooked. Missing and/or absent contractility or other forms of esophageal dysmotility leads to delayed treatment and interventions. Prolonged food bolus transit and stasis promote mucosal inflammation and remodeling, subsequently leading to neoplastic changes. We hope to increase awareness among emergency and internal medicine physicians of the prevalence of esophageal dysmotility disorders among patients with rheumatologic disease, and SLE specifically, to improve timing of diagnosis and interventions.

Persistently Rising Alpha-fetoprotein in the Diagnosis of Hepatocellular Carcinoma: A Review.

Hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide, is known for its grim prognosis, with untreated life expectancy being only a matter of months after the diagnosis. The difficulty in making a diagnosis early is one of the main contributing factors to the poor prognosis. Alpha-fetoprotein (AFP) had long been used as a surveillance tool, but suboptimal specificity and sensitivity has prompted liver societies to abandon the recommendation for its universal use, even in combination with ultrasonography. Most studies have shown no obvious correlation between serum AFP level and HCC tumor size, stage, or survival post-diagnosis. However, some studies concluded that a gradual rise or persistent elevation in AFP were positive predictors for tumor development. Other studies reported a fall in AFP followed by a rise in patients with HCC as well as persistently rising AFP levels without development of HCC on follow up. Our calculation of the sensitivity and specificity of persistently rising AFP for HCC were both low, at 60% and 35.8%, respectively, indicating that the presence of persistently rising AFP per se did not offer diagnostic benefit. In addition, our calculated mean slopes of persistently rising AFP levels in HCC and non-HCC patients were numerically very different, but the difference was not statistically significant. We conclude that the published data do not support a role for rising AFP levels per se in the diagnosis of HCC.

Advancing high-resolution manometry: evaluating the use of multiple rapid swallows versus apple viscous swallows in clinical practice.

BACKGROUND: High-Resolution Manometry (HRM) with provocative maneuvers, such as Multiple Rapid Swallows (MRS) and Apple Viscous Swallows (AVS), is commonly utilized to diagnose esophageal disorders. Increasing standardization in HRM protocol can help save time and reduce patient discomfort. This study assesses AVS and MRS to determine their respective benefits and limitations. METHODS: Retrospective reviews were performed on 100 patients to analyze their AVS and/or MRS results. Parameters included abnormal motility patterns, tolerance, and DCI. Diagnostic benefits from MRS and AVS were assessed. Based on the previous studies, additional benefit from MRS was defined as detection of good peristaltic reserve, weak peristaltic reserve, or an abnormal motility/pressurization pattern. Additional benefit from AVS was defined as detection of IEM features or abnormal motility/pressurization pattern. RESULTS: When patients completed both MRS and AVS (n = 70), MRS provided additional benefit in assessing 36% of patients, while AVS provided additional benefit in 19% of patients (p < 0.0001). Furthermore, MRS detected significantly more abnormal motility/pressurization patterns than AVS (27% MRS; 8% AVS; p = 0.0005). Two unique strengths of AVS were higher tolerance for test completion (p = 0.009) and better detection of severe hypokinetic disorders in 4% of patients, which were missed by MRS. CONCLUSIONS: MRS may uniquely identify abnormal motility/pressurization patterns, such as paradoxical LES response, distal pressurization, hypercontractile, and spasm patterns. These findings argue for a tailored approach when selecting provocative testing. MRS may be more useful for patients with abnormal pathophysiology, while AVS may help to supplement MRS in detecting severe hypokinetic disorders in preoperative management.

Response with pembrolizumab in a patient with EGFR mutated non-small cell lung cancer harbouring insertion mutations in V834L and L858R.

INTRODUCTION: Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC) being the most common of them. About a third of NSCLC cases have an epidermal growth factor (EGFR) mutation, which is usually susceptible to tyrosine kinase inhibitors (TKIs). In rare cases where patients progress through TKI therapy, the use of immune checkpoint inhibitors (ICIs) remains controversial. CASE REPORT: We describe a case of a patient with significant history of smoking and EGFR mutated programmed death ligand-1 (PD-L1) positive NSCLC who was initially treated with TKI therapy. MANAGEMENT/OUTCOME: While patient progressed on TKI therapy, he was able to achieve a durable response with a single PD-L1 agent, pembrolizumab. Contrary to the available evidence, the presented EGFR mutant NSCLC responded to PD-L1 pathway inhibition. DISCUSSION: From our observation Pembrolizumab could be promising in patients with rare EGFR mutations who do not respond to EGFR directed therapy. Our report provides supporting data for the use of immunotherapies in patients with EGFR mutated NSCLC.

Serrated lesions: A challenging enemy.

The serrated pathway accounts for 30%-35% of colorectal cancer (CRC). Unlike hyperplastic polyps, both sessile serrated lesions (SSLs) and traditional serrated adenomas are premalignant lesions, yet SSLs are considered to be the principal serrated precursor of CRCs. Serrated lesions represent a challenge in detection, classification, and removal-contributing to post-colonoscopy cancer. Therefore, it is of the utmost importance to characterize these lesions properly to ensure complete removal. A retrospective cohort study developed a diagnostic scoring system for SSLs to facilitate their detection endoscopically and subsequent removal. From the study, it can be ascertained that both indistinct border and mucus cap are essential in both recognizing and diagnosing serrated lesions. The proximal colon poses technical challenges for some endoscopists, which is why high-quality colonoscopy plays such an important role. The indistinct border of some SSLs poses another challenge due to difficult complete resection. Overall, it is imperative that gastroenterologists use the key features of mucus cap, indistinct borders, and size of at least five millimeters along with a high-quality colonoscopy and a good bowel preparation to improve the SSL detection rate.

Ethical dilemma of colorectal screening: What age should a screening colonoscopy start and stop?

Many advanced age patients who are diagnosed with colorectal cancer are often not offered surgical treatment due to presumed high risks of the procedure. While there is data to support surgical treatment of colorectal cancer in advanced age patients, screening colonoscopy is not currently recommended for patients older than 85 years. Moreover, recent studies concluded that the incidence of colorectal cancer in patients 80 years and older is increasing. This raises the concern that the current guidelines are withholding screening colonoscopy for healthy elderly patients. Another concern contrary to this would be the new trend of growing incidence of advanced colorectal cancer in the younger patient population. Together they raise the ethical dilemma of how to best utilize colonoscopies as well as surgical intervention, as they are limited resources.

Updates, Controversies, and Emerging Approaches in Colorectal Screening.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths. Despite the threatening statistics, the US burden for CRC has been decreasing, which is likely multifactorial and has partial contribution from widespread timely screening, more advanced CRC treatment, and daily aspirin use in some patients. While overall death rate from CRC decreased by approximately a half between 1975 and 2012, epidemiologic studies demonstrate that CRC incidence is increasing in the younger population. This pattern has prompted the American Cancer Society (ACS) to revise their guidelines. In this review, we plan to discuss the most recent changes in guidelines, data to support them, controversies concerning CRC screening methods, age to start and to stop screening, and post-colonoscopy/polypectomy surveillance guidelines.

Updates on the diagnosis, current and future therapeutic options in Merkel-cell carcinoma.

Merkel-cell carcinoma (MCC) is a rare and extremely aggressive nonmelanocytic cutaneous neuroendocrine carcinoma. Historically, it has been associated with limited therapy options and poor prognosis. While its incidence has been rising over the last two decades, recent discoveries and a better understanding of its pathogenesis, viral association and immunologic features have allowed for the emergence of new therapies. Surgical excision with or without radiotherapy remains the first-line therapy for primary lesions without evidence of metastatic disease. The majority of MCC cases are regrettably diagnosed at advanced stages and oftentimes require systemic therapy. There have been several significant advances in the treatment of MCC in the last decade. Among these have been the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death ligand-1 (PDL-1). Despite recent success of immunotherapy, nearly 50% of patients diagnosed with MCC still succumb to the disease. Fortunately, there has been a number of new targeted therapies that hold great promise. Among them are phosphatidylinositide-3kinase (Pl3K) inhibitors, adoptive T-cell immunotherapy, activated NK-92 cells infusions and therapeutic vaccines. Additional emerging therapeutic targets include cellular ubiquitin-specific processing protease 7 (Usp7) that restricts viral replication and IFN genes (STING), activation of which promotes an antitumor inflammatory response.

Ado-trastuzumab emtansine: Avoiding side-effects of traditional HER2 positive breast cancer treatment.

INTRODUCTION: Approach to cancer treatment is dictated by guidelines based on clinical research. New research continuously changes what we consider to be first-line therapy for a given type of cancer. Treatment approach becomes more complex when patient's cultural beliefs have to be considered and incorporated into the therapy. CASE REPORT: We are presenting a case of a patient born and raised in the former Soviet Union, whose understanding of how cancer should be treated was considerably different from what we now deem to be first-line therapy. This patient was diagnosed with metastatic HER2 positive breast cancer.Management and outcome: Having reservations about first-line therapy, she wanted to consider surgery as well as other lines of therapy. Her medical team worked on finding an alternative treatment plan that would be in line with her goals of care. Patient's personal beliefs led her to choose a therapy that is currently a second-line: Ado-trastuzumab emtansine. She was able to achieve full remission. DISCUSSION: Some recent studies discussed in this case showed that first-line therapies don't have significant progression free survival advantage when compared to the second-line therapy that our patient received. Ado-trastuzumab emtansine is a potent cytotoxic drug connected via a stable linker to the anti-HER2 antibody, trastuzumab. More studies need to be done to further investigate positive result presented in this case and whether this could be considered an alternative to current first-line therapy.

Post-renal transplant malignancies: Opportunities for prevention and early screening.

GOAL OF THE REVIEW: While transplant recipients are aware of increased malignancy risk, there is little consensus on the preventative measures. The goal of this review is to bring available preventative measures to light and prompt more research to be done with ultimate goal of developing an individualized prevention plan for each patient based on risk factors and available screening tools. INTRODUCTION: Transplant surgery offers patients with end-stage renal disease a longer life expectancy with help of immunosuppressive therapies. Nonetheless, life-long immunosuppression comes at a cost of post-renal transplant malignancies, which have become the leading cause of morbidity in this patient group. DISCUSSION: Post-renal transplant cancers can develop through either de novo, by donor-related transmission, or recurrence of recipient's pre-transplant cancer. While immunosuppressive therapy is considered to be the leading cause, weakened immunosurveillance of neoplastic cells and inadequate immune response against oncogenic viruses also plays an important role. The most common cancers seen in renal transplant patients are skin cancers and post-transplant lymphoproliferative disorder (PTLD). Risk factors for skin cancers have are ultraviolet light, human papilloma virus infection, and use of cyclosporin and azathioprine. Numerous viral infections have been associated with transplant-related malignancies post-transplant. CONCLUSION: While lowering of immunosuppressive therapy remains the treatment of choice, it may lead to graft failure. Given some of the presented malignancies have modifiable risk factors and options for screening, clinical outcomes can be improved. Limiting skin exposure, dermatologic screening, and prophylactic retinoids can help lower the incidence rate of skin malignancy. Endoscopic screening for renal transplant patients can help identify gastric adenocarcinoma early and improve survival rates. Some of the post-transplant malignancies have been responsive to anti-viral treatment.