This Month in Gastroenterology

Are patients with elevated liver tests at increased risk of drug-induced liver injury?

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Drug-Induced Liver Injury: Icelandic Lessons

INTRODUCTION: Recognition of Drug-induced Liver Injury (DILI) may be challenging as it is often diagnosis of exclusion, unavailability of diagnostic test and variability in presentation. Many antibiotics can cause DILI but Amoxicillin-Clavulanate has rare adverse reaction causing mixed cholestatic-hepatocellular injury. Since amoxicillin alone does not induce liver injury, combination of amoxicillin and clavulanic acid could be responsible for this adverse reaction. It can be due to metabolic idiosyncrasy or hypersensitivity mechanism. CASE DESCRIPTION/METHODS: 64-year-old female with no pertinent PMH presented to ER with abdominal pain and jaundice. She had abdominal pain for 4-5 days. Abdominal pain was constant and located at right upper quandrant and epigastric region. She had associated complaint of nausea, vomiting, metallic taste and chills. Patient had been avoiding eating in fear of vomiting. She also had pale colored stool. Patient did not have any history of gall stones, hepatitis or alcohol use. On further inquiry, she reported being on Amoxicillin-Clavulanate for 4 days, for dental abscess, before onset of symptoms. She stopped taking antibiotic as soon as she started having above-mentioned symptoms. Patient was not on any other new medications during this time-period. On initial evaluation, patient was found to have elevated liver enzymes with T.bilirubin 6.4, AST 218, ALT 288, ALP 331. Due to broad differentials associated with elevated liver enzymes with abdominal pain, further workup was done. Abdominal CT scan and MRCP results were unremarkable. Hepatitis panel was also negative. Patient was provided with supportive care and hydration with IV fluids. Repeat labs done on 4th day after admission showed down trending LFTs – T.bill 3.8, AST 152, ALT 141, ALP 253. DISCUSSION: Amoxicillin-Clavulanate can cause hepatocellular, cholestasis or mix type of liver injuries depending upon genetic factors or pre-existing liver conditions. Early recognition and removal of offending medication is the initial mainstay of treatment along with supportive care. This case signifies proper history taking and review of medications could avoid unnecessary and expensive diagnostic tests for diagnosis. Our case emphasis importance of early recognition of this reversible condition due to Amoxicillin-Clavulanate or other medications to prevent worsening of liver faliure and its complication.

INTRODUCTION: The severity of drug-induced liver injury (DILI), a diagnosis of exclusion, can vary greatly from mild to life-threatening. Allopurinol is a commonly used medication that rarely causes serious hepatotoxicity. Objective data, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total serum bilirubin, have been used to grade the severity of liver injury. We present a case of idiosyncratic allopurinol-induced cholestatic injury that meets diagnostic criteria for severe and life-threatening. CASE DESCRIPTION/METHODS: A 70-year-old African American woman with gouty arthritis, hypertension, and dyslipidemia presented to the Emergency Room with two weeks of abdominal pain. The patient was started on allopurinol for acute gout flare one month prior to presentation. In the interim, she developed malaise, anorexia (3 kg weight loss), and pruritus. She had no personal or family history of liver disease. Physical examination was notable for scleral icterus and mild, diffuse abdominal tenderness. Complete blood count was remarkable for absolute eosinophilia of 3.0 thou/cu mm, confirmed on peripheral blood smear. Liver function tests revealed a cholestatic pattern, with AST 259 u/L (normal 5-34), ALT 411 u/L (10-60), ALP 817 u/L (4-121), GGT 766 u/L (9-36), total bilirubin 15.7 mg/dL (0.2-1.2) and direct bilirubin 10.6 mg/dL (0.1-0.5). Synthetic liver function was normal. Toxicology screens, ceruloplasmin level, hepatitis serologies, and autoimmune workup were unremarkable. Imaging studies did not reveal acute pathology. Liver biopsy showed mild/moderate expansion of mixed inflammatory infiltrate with increased number of eosinophils. After discontinuation of allopurinol, absolute eosinophil count and liver function tests trended down with clinical resolution of symptoms. DISCUSSION: Among DILI literature, few reports exist of severe, life-threatening cholestatic liver injury after allopurinol initiation. This patient had 8x the upper limit of normal AST, 7x ALT, 7x ALP, 21x GGT, and 21x direct bilirubin. According to multiple DILI severity grading tools, this case is classified between severe (grade 3) and life-threatening (grade 4). Beyond discontinuation of the medication, there are limited treatment options available for idiosyncratic DILI other than liver transplantation. Therefore, prompt discontinuation of the offending medication along with close monitoring for progression to fulminant liver failure is crucial.

The WHO published a new classification of colonic polyps in 2010, including the group of serrated polyps, which can be divided into hyperplastic polyps (HP), traditional serrated adenomas, and sessile serrated adenomas (SSA) or polyps. To assess the rate of re-diagnosis of HP to SSA and to look for possible predictors for changing the diagnosis. English Medical literature searches were performed for 'reassessment' OR 'reclassification' AND 'hyperplastic polyp' OR 'sessile serrated adenoma' till 31 January 2017. PRISMA guidelines for systematic reviews were followed. Studies that included a precise re-diagnosis of HP into SSA were included. We also looked for predictors of SSA diagnosis such as polyp location and size, patient sex and age, and synchronous advanced adenoma. Altogether, we found 220 eligible studies; 212 were excluded as they did not fulfill the inclusion criteria and we were left with eight studies including 2625 patients. The odds ratio for the number of polyps with changed pathological diagnosis from HP to SSA was 0.112 with 95% confidence interval (CI): 0.099-0.126 (P<0.0001) or 11.2%. Heterogeneity between studies was significant with Q=199.4, d.f. (Q)=9, P<0.0001, and I=95.486%. The odds ratio for changing the pathological diagnosis from HP to SSA for polyp proximal location and polyp size more than 5 mm were 4.401, 95% CI: 2.784-6.958, P<0.0001, and 8.336, 95% CI: 4.963-15.571, P<0.0001, respectively. Endoscopists and pathologists should be aware of the SSA diagnosis when finding HPs larger than 5 mm in the right colon. The diagnosis of HP in these cases should be reassessed by experienced gastrointestinal pathologists.

Sessile serrated lesions (SSL) are precursors to colon carcinoma, and their distinction from other polyps, in particular hyperplastic polyps (HP), presents significant diagnostic challenges. We evaluated expression patterns in colonic polyps of previously identified colon carcinoma-associated extracellular matrix (ECM) proteins to identify markers distinguishing SSLs from other polyps. Gene-expression analyses of ECM proteins were performed using publicly available data on preneoplastic colonic polyps. In parallel, we evaluated by IHC the expression of agrin (AGRN) in over 400 colonic polyps, including HP, SSL with and without dysplasia, traditional serrated adenomas (TSA), and tubular adenomas (TA), and compared the consistency of standard histologic diagnosis of SSLs by experienced gastrointestinal pathologists with that of AGRN IHC. Differential gene expression analysis and IHC identified AGRN, serine peptidase inhibitor (SERPINE2), and TIMP metallopeptidase inhibitor 1 (TIMP1) elevated in SSLs and HPs but decreased in TAs and absent in normal colon. AGRN-positive basal laminae were noted in all TA, TSA, HP, and SSL in distinguishable patterns, whereas other polyps and normal mucosa were negative. SSL with or without dysplasia consistently showed IHC staining for AGRN in the muscularis mucosae, which was absent in HP, TSA, TA, and other polyps. In contrast, histologic evaluation showed only weak interobserver agreement (kappa value = 0.493) in distinguishing SSLs. Muscularis mucosae-based AGRN immunostaining is a novel biomarker to distinguish SSL from HP, TSA, and TA, with a specificity of 97.1% and sensitivity of 98.9% and can assist in diagnosis of morphologically challenging colonic polyps.

Sessile serrated adenomas: high-risk lesions?

Survivin and hedgehog protein expression in serrated colorectal polyps: an immunohistochemical study

Aim: Sessile serrated lesions (SSL) have the potential for malignant transformation into colorectal carcinoma (CRC), which develops via the serrated pathway of carcinogenesis. Material and Methods: Based on colonoscopy and pathology reports, all sessile serrated lesions or polyps in the risk screening group were studied at an urban medical research center between July 2018 and July 2022. We prospectively included consecutive colorectal polyps classified as a hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), unclassified serrated adenoma, and synchronous neoplasm or polyp. Results: During the 48-month study period, 167 cases of sessile serrated lesions or polyps were diagnosed. In the study, 97 (58.1%) of the patients were male, 70 were female (41.9%), and the mean age was 59.74 (± 11.1). Hematoxylin-eosin preparations were available for complete analysis for 226 SSL, and 117 had synchronous adenomatous polyps or carcinomas. Approximately 88.1% of all polyps were ≤10 mm or less in diameter. There was a significant correlation between polyp size (≤10 mm) and epithelial polyps (p=0.000). In particular, polyps detected in the sigmoid colon with the rectum were relatively larger than in other locations. The sigmoid colon and rectum were the most common locations for sessile serrated lesions in our study. There was a significant association between epithelial polyps and anatomical locations (p=0.000). The distribution of all epithelial polyps was as follows; HP was the most frequently observed epithelial polyp with 57.7% (194 polyps), SSL was 6.8% (23 polyps), and TSA was 2.1% (7 polyps), unclassified serrated adenoma was 0.6% (2 cases), synchronous conventional were seen in 31% (104 polyps) of SSL or polyps, and carcinoma with polyps was detected in three (0.9%) cases Conclusions: Hyperplastic polyps are the most common sessile serrated lesions, and synchronous conventional tubular adenomas were most commonly accompanied by hyperplastic polyps. HPs were most commonly observed in the distal colon, particularly in the sigmoid colon and rectum. Future prospective studies using uniform diagnostic criteria and considering clinical outcomes are needed to make accurate decisions regarding surveillance and treatment of patients with serrated lesions.

Introduction: Drug induced liver injury or DILI is any injury to the liver by a medication, herb, or dietary supplement. Ranking as the first cause of acute liver failure in the USA and Europe, spectrum of clinical presentation may range from asymptomatic elevated liver function test to ALF. Approximately 20 new cases of DILI per 100,000 persons occur each year worldwide. Classified as intrinsic (with the most common cause being acetaminophen), and idiosyncratic adverse drug reaction (including mostly those related to antibiotics, NSAID drugs, and isoniazid). Isotretinoin is indicated to treat severe inflammatory acne that is refractory to antibiotics or topical agents; Although it has a high margin of safety, adverse effects include transaminasitis, like many retinoids, but unlike acitretin and etretinate, isotretinoin has not been clearly implicated in cases of clinically apparent acute liver failure. We report a case of 31 year old lady on isotretinoin therapy for her acnea since 8 month with poor follow up, presenting with acute liver failure to our emergency department. Case Presentation: 31 year old lady , NKDFA, on isotretinoin for her acne, started 8 month ago at a dose 40mg daily, is brought by her family for decrease level of consciousness and increasing jaundice since around 5 days associated with mild abdominal disconfort. Intubated for GCS of 3, laboratory tests showed prolonged INR and elevated total bilirubin, mainly direct, with elevated transaminase levels, all work up for other etiologies turned negative, and patient was diagnosed with isotretinoin inducing acute liver failure. Discussion: Hepatotoxicity manifesting by liver test abnormalities, occur in up to 15% of patients on isotretinoin. These liver test abnormalities are usually asymptomatic and resolve spontaneously even without discontinuation of therapy in most cases. Severe liver injury due to isotretinoin is exceedingly rare: The acute liver failure was only been described with etretinate and acitretin and not with isotretinoin therapy. Risk factors for DILI include older age, female sex, African American, pharmacological risk (including daily dosage, degree of lipophilicity and extent of hepatic metabolism), preexisting liver disease and Host Genetic Factors. An important association was found between the dose of oral medication and hepatotoxicity in the United States and Sweden, in addition to a positive association between higher drug lipophilicity and DILI in condition to be coupled with high dose ingestion. Our patient meets the criteria for sex and for the pharmacological characteristic of isotretinoin (which is a highly lipophilic drug and was ingested at 40mg daily). DILI may cause cholestatic or hepatocellular liver injury or mixed on the basis of the R value, In addition, studies have showed that DILI in females is more often hepatocellular and may be associated with a more severe course, which can result in the need for liver transplant, or death and all that were compatible with our case. As the disorder is rare, there are no specific biomarkers for diagnosis of idiosyncratic DILI, and diagnosis is made by exclusion. Recent advances in the diagnosis of DILI include the recognition of the importance of the establishment of clinical networks to refine causality assessment estimated by RUCAM score and also the use of expert panels in the diagnosis of DILI [3]. The calculated RUCAM score for our case is equal to 8, indicating probable drug reaction. Concerning acute liver failure, the most widely accepted definition from the American Association for the Study of Liver Diseases (AASLD) is ‘’evidence of coagulation abnormality, usually an international normalized ratio above 1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting liver disease and with an illness of less than 26 weeks’ duration’’. Based on all above, the presentation of our patient was typical for an acute liver failure induced by the drug isotretinoin. The only curative treatment of drug induced acute liver failure is liver transplantation. Conclusion: This is probably the first case reporting an acute liver failure induced by isotretinoin therapy. Strict monitoring of liver tests is highly recommended for patients receiving isotretinoin at regular intervals, with close observation and follow up, because, although rare, it may induce an acute liver failure with deleterious results. Future works must include a discovery of an early markers of DILI, for early detection and prevention in the high risk patients.

Ayurvedic and herbal medicines (AHM) are known to cause varying degrees of drug-induced liver injury (DILI). Clinical, biochemical, histological spectrum and outcomes of AHM linked to severe DILI are not well studied. Out of 1440 liver disease patients, 94 were found to have a severe liver injury and associated AHM intake. Thirty-three patients were suspected to have AHM-DILI on Roussel Uclaf Causality Assessment Scoring Method. Forty-seven and 30 of retrieved AHM samples were analyzed for heavy metals and hepatotoxic volatile organic compounds (hVOCs), respectively. Eleven patients ingested AHM from unregistered traditional healers (UTH). Clinicopathological outcomes were analyzed in 27 patients (who underwent liver biopsy) and outcomes with respect to chemical analyses were studied in 33 patients. Males predominated (70.4%) with mean age 46.9±15.8 years. Mean follow up was 119.2±81.4 days. The median duration of drug intake was 28days (10 - 84). Five patients died (18.5%). Hepatic encephalopathy, hypoalbuminemia, and hepatic necrosis were significantly associated with mortality (p < 0.005). Arsenic and mercury ingestion was significantly associated with death (p < 0.005). hVOCs were detected in more than 70% of samples. AHM intake from UTH was associated with higher mortality. Adequate regulation and scrutiny regarding AHM use among the general population is an unmet need. Early liver biopsy after clinical identification of at-risk patients can expedite definitive treatment with a liver transplant.

Hyperplastic polyps, once considered to have no malignant potential, are now recognized to be part of a larger group of polyps known as serrated polyps. Serrated polyps can progress to CRC through an epigenetic pathway known as CpG Island Methylator Phenotype (CIMP), characterized by hypermethylation of specific DNA regions such as the promoter regions of the DNA mismatch repair genes like MLH1. The CIMP pathway is tightly linked with mutations of the oncogene BRAF. There are three subtypes of serrated polyps - hyperplastic polyps, sessile serrated polyps (SSPs) and traditional serrated adenomas (TSAs). TSAs harbor cytologic dysplasia whereas hyperplastic polyps and SSPs are nondysplastic lesions. Currently, only SSPs and TSAs are believed to progress to CRC whereas hyperplastic polyps are thought to be benign with no malignant potential. This article will review the current evidence while highlighting some of the issues regarding serrated polyps. One challenge has been pathologically distinguishing hyperplastic polyps from SSPs, which is an important distinction, given the potential for progression of SSPs to CRC. Other challenges regarding serrated polyps include adequate detection and resection. Surveillance guideline recommendations for some serrated polyps have been changed in current guidelines to reflect the malignant potential, recommending closer surveillance intervals than the 10-year follow-up that has been traditionally provided for hyperplastic polyps. Given the difficulties in diagnosing as well as resecting, it is important for endoscopists to know how to detect, resect and manage follow-up in patients with serrated polyps.

Introduction: Sessile serrated adenomas (SSAs) are important colorectal cancer (CRC) precursor lesions. Due to changing pathologic definitions and criteria, patients with SSAs may be misclassified as having hyperplastic polyps (HPs), particularly in older studies. Surrogate definitions of important serrated polyps such as large or proximal HPs are imperfect, as not all these polyps have malignant potential. We sought to estimate the true proportion of proximal and large HPs that are actually SSAs. Methods: Using pooled data from a series of cross-sectional studies of patients undergoing colonoscopic screening between 1998 and 2010 at the University of North Carolina, we identified patients with proximal HPs and HPs ≥5 mm. Polyps were then reviewed by an expert pathologist using established pathological criteria to determine the presence of SSAs. Data on polyp size, location, and synchronous polyps were abstracted from colonoscopy and pathology reports. Results: Among 2,308 patients undergoing colonoscopy, we identified 532 with lesions initially diagnosed as HPs (23%). One hundred seventy-six patients had proximal HPs, and 126 had HPs ≥5 mm. A total of 191 patients (8%) had either large or proximal HPs and were submitted for pathology review. Among these, 78 patients had at least 1 SSA (41%), and 6 had SSAs with cytological dysplasia. Half of SSAs were associated with synchronous conventional adenomas, and 22 patients (28%) had multiple SSAs (range: 2-12); 55% of those with SSAs were male. The proportion of polyps that were SSAs increased slightly over time (SSAs represented 2.8%, 3.2%, and 4.1% of polyps in 1998-2000, 2001-2005, and 2006-2010, respectively). Compared to reviewed polyps that were confirmed to be HPs, SSAs were larger (mean size 6.4 vs. 4.5 mm; p<0.001), more proximally located (83% vs. 69%; p=0.03), and were more commonly associated with a positive family history of CRC (17% vs. 6%; p=0.03). Conclusion: Patients with SSAs represented roughly 40% of those with proximal or large serrated polyps in this study. Predictors of SSAs among this group included larger size, proximal location, and family history of CRC. These data may aid gastroenterologists to risk stratify and assign appropriate surveillance intervals to patients with large or proximal HPs found on colonoscopy.Table 1: Characteristics of Patients With SSAs

ObjectiveTo identify modifiable factors associated with sessile serrated polyps (SSPs) and compare the association of these factors with conventional adenomas (ADs) and hyperplastic polyps (HPs).DesignWe used data from the Tennessee...