Persistent diarrhea with petechial rash - unusual pattern of light chain amyloidosis deposition on skin and gastrointestinal biopsies: A case report.

BACKGROUND: Amyloidosis is a rare disease characterized by extracellular deposition of misfolded protein aggregated into insoluble fibrils. Gastrointestinal involvement in systemic amyloidosis is common, but is often subclinical or presents as vague and nonspecific symptoms. It is rare for gastrointestinal symptoms to be the main presenting symptom in patients with systemic amyloidosis, causing it to be undiagnosed until late-stage disease. CASE SUMMARY: A 53 year-old man with diarrhea, hematochezia, and weight loss presented to a community hospital. Colonoscopy with biopsy at that time was suspicious for Crohn disease. Due to worsening symptoms including nausea, vomiting, and a new petechial rash, an abdominal fat pad biopsy was done. The biopsy showed papillary and adnexal dermal amyloid deposition, in a pattern usually seen with cutaneous amyloidosis. However, Cytokeratin 5/6 was negative, excluding cutaneous amyloidosis. The patterns of nodular amyloidosis, subcutaneous amyloid deposits and perivascular amyloid were not seen. Periodic Acid-Schiff stain was negative for lipoid proteinosis, Congo red was positive for apple green birefringence on polarization and amyloid typing confirmed amyloid light chain amyloidosis. Repeat endoscopic biopsies of the gastrointestinal tract showed amyloid deposition from the esophagus to the rectum, in a pattern usually seen in serum amyloid A in the setting of chronic inflammatory diseases, including severe inflammatory bowel disease. Bone marrow biopsy showed kappa-restricted plasma cell neoplasm. CONCLUSION: Described is an unusual presentation of primary systemic amyloidosis, highlighting the risk of misdiagnosis with subsequent significant organ dysfunction and high mortality.

Vanishing Bile Duct Syndrome Associated With Estrogen.

Vanishing bile duct syndrome (VBDS) refers to a form of cholestatic liver disease with many etiologies. Vanishing bile duct syndrome is characterized by biliary ductopenia and chronic cholestasis. This is a challenging condition for clinicians because of its rarity and unclear pathophysiology. Presented is an 18-year-old woman who developed cholestatic liver injury and intrahepatic biliary ductopenia after a course of oral contraceptives and intravenous estrogen for uterine bleeding. A year later, this patient did not have significant improvement in liver biomarkers and was referred for transplantation.

A Case of Macroenzyme Aspartate Aminotransferase Mimicking Hepatic Injury.

Macroenzymes are high molecular weight complexes that are formed by the binding of normal serum enzymes with circulating immunoglobulins - primarily IgG, IgA, and IgM. These high molecular weight complexes are difficult to clear through the kidneys, therefore they remain persistently elevated in the serum leading to inaccurate diagnoses and unnecessary workup. The prevalence of macroenzymes is relatively rare in the general population; however, it is an important phenomenon to be aware of when working up isolated elevations in serum enzymes. A quick and efficient test for the detection of macroenzymes is the polyethylene glycol precipitation test. Here, we present a case of macro-aspartate aminotransferase masquerading as an underlying hepatobiliary disease ultimately leading to an extensive evaluation before arriving at the correct diagnosis. This case highlights the importance of an accurate and efficient diagnosis of macroenzymes in the serum in order to prevent unnecessary healthcare utilization and also to decrease the psychological burden on the patient.

Everolimus with early withdrawal or reduced-dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta-analysis.

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal-sparing effect. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75-17.8). EVR use was not associated with an increased risk of biopsy-proven acute rejection (RR 0.68, 95% CI: 0.31-1.46), graft loss (RR 1.60, 95% CI: 0.51-5.00), or mortality (RR 1.34, 95% CI 0.62-2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10-1.91).

Direct acting antiviral therapy is curative for chronic hepatitis C/autoimmune hepatitis overlap syndrome.

Autoimmune phenomena are common in patients with chronic hepatitis C. Management of chronic hepatitis C/autoimmune hepatitis syndrome has until recently been problematic due to the adverse effects of interferon on autoimmune processes and immunosuppression on viral replication. In this report we describe 3 patients with chronic hepatitis C/autoimmune hepatitis overlap syndrome who responded rapidly to direct acting anti-viral therapy. The resolution of the autoimmune process supports a direct viral role in its pathophysiology.

Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients.

Depression, common in chronic medical conditions, and hepatic encephalopathy (HE), a reversible neuropsychiatric syndrome due to liver dysfunction, are associated with impaired health-related quality of life (HRQOL) in cirrhosis and hepatitis C (HCV). This study investigated the impact of depression and HE on HRQOL in cirrhotic patients with HCV. A convenience sample of 43 ambulatory patients, with varying degrees of cirrhosis secondary to HCV, was prospectively enrolled in this study. Participants were assessed for any current depressive, fatigue, and daytime sleepiness symptoms and underwent a psychometric evaluation to determine the presence of HE symptoms. Participants reported current HRQOL on general health and liver disease-specific questionnaires. Diagnosis and current health status were confirmed via medical records. The associations between disease severity, depressive symptoms, HE, fatigue, and daytime sleepiness were measured. Predictors of HRQOL in this sample were determined. Depressive symptoms (70 %) and HE (77 %) were highly prevalent in this sample, with 58 % actively experiencing both conditions at the time of study participation. A significant positive association was found between depressive symptoms and HE severity (P = .05). Depressive symptoms were significantly associated with fatigue (P < .001), daytime sleepiness (P < .001), general HRQOL (P < .001), and disease-specific HRQOL (P < .001). HE was significantly associated with fatigue (P = .02), general HRQOL (P < .001), and disease-specific HRQOL (P < .001). Depressive symptoms and HE were significant predictors of reduced HRQOL (P < .001), with depressive symptoms alone accounting for 58.8 % of the variance. Depressive symptoms and HE accounted for 68.0 % of the variance. Findings suggest a possible pathophysiological link between depression and HE in cirrhosis, and potentially a wider-reaching benefit of treating minimal and overt HE than previously appreciated.

The Effect of Colonoscopy Reimbursement Reductions on Gastroenterologist Practice Behavior.

GOAL: The purpose of this study was to assess the effect of decreased colonoscopy reimbursement on gastroenterologist practice behavior, including time to retirement and procedure volume. BACKGROUND: In 2015, the Centers for Medicare and Medicaid Services proposed reductions in colonoscopy reimbursements. With new initiatives for increased colorectal cancer screening, it is crucial to understand how reimbursement changes could affect these efforts. STUDY: Randomly selected respondents from the American College of Gastroenterology membership database were surveyed on incremental changes in practice behavior if colonoscopy reimbursement were to decrease by 10, 20, 30, or 40 %. Data were analyzed using both Pearson's Chi-square and analysis of variance. RESULTS: Two thousand and nine gastroenterologists received the survey with a 16.3 % response rate. Procedure volume significantly decreased with degree of reimbursement reductions (p < 0.001). With a 10 % decrease, 72 % of respondents reported no change in the number of colonoscopies performed. With a 20 % decrease, 39 % would decrease their procedure volume, while 21 % of respondents would increase their procedure volume. With a 30 and 40 % decrease, procedure volume decreased by 48 and 50 %, respectively. In terms of retirement, current plans predict a cumulative retirement rate of 29.4 % at 10 years. More than 42 % of respondents plan to retire after 2030. In the 2014-2023 retirement subgroup (N = 74 responses), there was a significant hastening of retirement year at 20 % (p = 0.016), 30 % (p < 0.001), and 40 % (p < 0.001) reimbursement reductions as compared to baseline responses. CONCLUSION: Decreasing colonoscopy reimbursements may have a significant effect on the effective gastroenterology work force.

Autoimmune hepatitis.

Autoimmune hepatitis is a chronic liver disease putatively caused by loss of tolerance to hepatocyte-specific autoantigens. It is characterized by female predilection, elevated aminotransferase levels, autoantibodies, increased γ-globulin or IgG levels and biopsy evidence of interface hepatitis. It is currently divided into types 1 and 2, based on expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2. Although autoimmune hepatitis occurs in childhood, this review focuses on disease in adults. In the absence of pathognomonic biomarkers, diagnosis requires consideration of clinical, biochemical, serological and histological features, which have been codified into validated diagnostic scoring systems. Since many features also occur in other chronic liver diseases, these scoring systems aid evaluation of the differential diagnosis. New practice guidelines have redefined criteria for remission to include complete biochemical and histological normalization on immunosuppressive therapy. Immunosuppression is most often successful using prednisone or prednisolone and azathioprine; however, the combination of budesonide and azathioprine for non-cirrhotic patients offers distinct advantages. Patients failing standard immunosuppression are candidates for alternative immunosuppressive regimens, yet none of the options has been studied in a randomized, controlled trial. Overlap syndromes with either primary sclerosing cholangitis or primary biliary cirrhosis occur in a minority. Liver transplantation represents a life-saving option for patients presenting with acute liver failure, severely decompensated cirrhosis or hepatocellular carcinoma. Transplant recipients are at risk for recurrent autoimmune hepatitis in the allograft, and de novo disease may occur in patients transplanted for other indications. Patients transplanted for AIH are also at risk for recurrent or de novo inflammatory bowel disease. Progress in our understanding of the immunopathogenesis should lead to identification of specific diagnostic and prognostic biomarkers and new therapeutic strategies.

Elucidating the spectrum of alpha-thalassemia mutations in Iran.

Alpha thalassemia (alpha-thal) is one of the most common hemoglobin (Hb) disorders in the world. Alpha-globin genes are located on chromosome 16. The majority of alpha-thal mutations are deletions but point mutations are found as well. Since the Iranian population is a mixture of different ethnic groups, frequency and distribution of alpha-globin mutations in various regions of the country need to be clarified. These findings can contribute to a wider understanding of this disorder.

Fourteen-year experience of prenatal diagnosis of thalassemia in Iran.

For 14 years, Iranian scientists have worked to develop a national thalassemia prevention program. Although historically abortion was considered unacceptable in Iran, intensive consultations led to the clerical approval of induced abortion in cases with beta-thalassemia major in 1997, and a nationwide prevention program with screening, counseling and prenatal diagnosis (PND) networks has been developed. This paper reports the experience from one of the two national PND reference laboratories. As one of the oldest reference laboratories, we performed a total of 906 PND in 360 couples at risk for thalassemia from 1990 to 2003. Direct and indirect mutation detection methods were applied for all cases. In total, 22 mutations were tested routinely, and an additional 30 rare mutations were identified. 208 fetuses were found to be normal, 215 fetuses had beta-thalassemia major, and 435 fetuses were carriers of the trait. In 40 cases, we only defined one allele. In 8 cases, we were unable to provide any diagnosis, corresponding to 0.9%. Our data support the functionality of the Iranian beta-thalassemia prevention program. The success of this system in Iran, a multiethnic and Islamic-based country, would mean that it might be applied as an adaptive system for neighboring and other Islamic countries.

The Iranian Human Mutation Gene Bank: a data and sample resource for worldwide collaborative genetics research.

As Human Genome Project exploration continues, the necessity of having a broader spectrum of genomic DNA material from different nationalities to study various aspects of hereditary disease becomes more obvious. The existence of high genetic polymorphism within and between different communities in the world makes it necessary for the gene hunters to investigate many different populations. Iran, a large country with close to 66 million people, is a land of different nationalities, tribes, and religions that offers a highly heterogeneous gene pool to the genetics researcher. The purity of many different races in this country has been highly conserved by geographical borders and by an ancient culture that has always encouraged intrafamilial marriages. All these have created a population that is remarkably heterogeneous yet high in consanguinity rate. During the last five years of investigation we have established a DNA bank, the Iranian Human Mutation Gene Bank (www.IHMGB.com), which contains all genetic diseases studied in Iran that have the Mendelian mode of inheritance. Some of the samples are assigned to common or novel mutations and others belong to patients with clinical profiles associated with particular genetic diseases but undefined mutation. This bank stores samples of DNA from the patient and his/her first-degree relatives together with a comprehensive pedigree and clinical profile for each sample. To facilitate collaboration with other scientists around the world with the same interests, we decided to present our experimental projects online. This DNA bank provides opportunities for us to collaborate with scientists outside Iran. It offers a sample resource to research scientists around the world, at no charge, for the purpose of investigating the various aspects of genetic disorders from prenatal diagnosis to gene structure and function. It is strongly stressed that no commercial benefit is involved in the establishment of this DNA bank and the DNA samples are free of charge. However, to meet our goals and to respect ethical values, DNA samples can only be used under certain conditions stated in the User Consent Form.

The preventive effect of captopril or enalapril on reperfusion injury of the kidney of rats is independent of angiotensin II AT1 receptors.

Occlusion of the artery of organs results in ischaemia. The opening of occluded artery results in tissue lesion identified as reperfusion injury (RI). Renin-angiotensin system seems to be involved in the RI. In this study we assessed the effects of different doses of two inhibitors of angiotensin converting enzyme (captopril or enalapril) and an angiotensin receptor type 1 (AT1) receptor blocker (losartan) in the RI of the kidney of rats. Female rats of 200-250 g were anaesthetized and used for RI studies. Different doses of captopril (5, 20 and 80 mg/kg), enalapril (1, 4 and 16 mg/kg) and/or losartan (5, 10 and 20 mg/kg) were used (s.c.) 120 min prior to the initiation of RI. Kidneys were removed and checked histologically for the presence and the grading of ischaemic injury. Appropriate controls were used as well, RI produced lesions comparable with that of ischaemia. Different doses of captopril or enalapril prevented these lesions. This is suggestive of the involvement of renin-angiotensin system in the RI. Different doses of losartan failed to prevent RI lesions which suggest that the effect of captopril or enalapril are not mediated through the AT1 receptors. Further studies on the involvement of AT2 receptor or other independent mechanisms are suggested.