Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury.

BACKGROUND & AIMS: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. RESULTS: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10-6). CONCLUSIONS: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. CLINICAL TRIALS: gov number: NCT00345930.

Flavin Adenine Dinucleotide Depletion Caused by electron transfer flavoprotein subunit alpha Haploinsufficiency Leads to Hepatic Steatosis and Injury in Zebrafish.

The electron transfer flavoprotein (ETF) complex, made up of the ETF alpha subunit (ETFA), ETF beta subunit (ETFB), and ETF dehydrogenase (ETFDH), regulates fatty acid ß-oxidation activity while scavenging leaked electrons through flavin adenine dinucleotide (FAD)/reduced form FAD (FADH2) redox reactions in mitochondria. Here, we hypothesized that ETF dysfunction-mediated FAD deficiency may result in increased mitochondrial oxidative stress and steatosis and subsequent liver injury. We report that etfa haploinsufficiency caused hyperlipidemia, hypercholesterolemia, and hepatic steatosis and injury in adult zebrafish. Further, etfa+/ - mutant livers had reduced levels of FAD and glutathione and an increase in reactive oxygen species. Because FAD depletion might be critical in the pathogenesis of the liver lesion identified in etfa+/ - mutants, we used riboflavin to elevate FAD levels in the liver and found that riboflavin supplementation significantly suppressed hepatic steatosis and injury in etfa+/ - mutants through suppression of oxidative stress and de novo lipogenesis in the liver. Additionally, we found that adenosine triphosphate-linked mitochondrial oxygen consumption and mitochondrial membrane potential were reduced in etfa+/ - primary hepatocytes and that riboflavin supplementation corrected these defects. Conclusion: FAD depletion caused by etfa haploinsufficiency plays a key role in hepatic steatosis and oxidative stress-mediated hepatic injury in adult zebrafish. This raises the possibility that people with ETFA haploinsufficiency have a high risk for developing liver disease.

HLA-B*35:01 and Green Tea-Induced Liver Injury.

BACKGROUND AND AIMS: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Drug-Induced Liver Injury Caused by Kratom Use as an Alternative Pain Treatment Amid an Ongoing Opioid Epidemic.

Kratom ( Mitragyna speciosa) is a prevalent medicinal plant used mainly for the stimulant and analgesic properties provided through multiple alkaloid compounds. Over the past decade, use of kratom has increased despite the limited knowledge of toxicities and adverse side effects. With the current opioid epidemic, both patients and providers are seeking alternative methods to treat both addiction and pain control, and kratom as an alternative means of treatment has increasingly entered the mainstream. In this article, we present the clinical course of a 47-year-old male who developed fatigue, pruritus, and abnormal liver tests (with a mixed hepatocellular/cholestatic pattern) approximately 21 days after beginning kratom. After extensive evaluation including a negligible alcohol history, negative hepatitis serologies, and inconclusive imaging, the patient was diagnosed with drug-induced liver injury (DILI) caused by kratom. Nine months after his liver tests returned to normal, he took kratom again, and after a latency of 2 days, he developed fatigue, pruritus, and loss of appetite along with abnormal liver tests (with the same biochemical profile as previously), consistent with a positive rechallenge. We believe, through the use of the Roussel-Uclaf Causality Assessment Method and expert opinion, that this is a highly likely or definite example of kratom-induced DILI. With the gaining popularity of this drug, it appears that DILI may be an important complication of kratom for providers to recognize.

Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the Drug-Induced Liver Injury Network (DILIN).

BACKGROUND & AIMS: Because of the lack of objective tests to diagnose drug-induced liver injury (DILI), causality assessment is a matter of debate. Expert opinion is often used in research and industry, but its test-retest reliability is unknown. To determine the test-retest reliability of the expert opinion process used by the Drug-Induced Liver Injury Network (DILIN). METHODS: Three DILIN hepatologists adjudicate suspected hepatotoxicity cases to one of five categories representing levels of likelihood of DILI. Adjudication is based on retrospective assessment of gathered case data that include prospective follow-up information. One hundred randomly selected DILIN cases were re-assessed using the same processes for initial assessment but by three different reviewers in 92% of cases. RESULTS: The median time between assessments was 938 days (range 140-2352). Thirty-one cases involved >1 agent. Weighted kappa statistics for overall case and individual agent category agreement were 0.60 (95% CI: 0.50-0.71) and 0.60 (0.52-0.68) respectively. Overall case adjudications were within one category of each other 93% of the time, while 5% differed by two categories and 2% differed by three categories. Fourteen per cent crossed the 50% threshold of likelihood owing to competing diagnoses or atypical timing between drug exposure and injury. CONCLUSIONS: The DILIN expert opinion causality assessment method has moderate interobserver reliability but very good agreement within one category. A small but important proportion of cases could not be reliably diagnosed as ≥50% likely to be DILI.

Predictors of endoscopic and laboratory evaluation of iron deficiency anemia in hospitalized patients.

BACKGROUND: Many hospitalized anemic patients do not undergo appropriate evaluation. We hypothesized that specific clinical variables were likely to be important in triggering evaluation for iron deficiency anemia. METHODS: We prospectively identified 637 consecutive anemic patients without acute gastrointestinal bleeding admitted over a three-month period to medical inpatient teams of two teaching hospitals and examined clinical variables that predicted diagnostic evaluation. RESULTS: Serum ferritin or serum transferrin saturation (TS) were measured in 43% (271/637) of subjects and were low in 38% (102/271). Predictors of serum ferritin or TS measurement included low hemoglobin concentration and a history of iron supplementation. Predictors of iron deficiency included low hemoglobin concentration (OR 1.9, 95% CI 1.06-3.5) and low mean cell volume (OR 4.6, 95% CI 2.5-8.6). Of 102 patients with iron deficiency anemia, 31% underwent endoscopic evaluation, and 39% had serious gastrointestinal lesions. The only significant predictor of having an endoscopic evaluation was a positive fecal occult blood test (FOBT) (OR 5.2, 95% CI 1.7-16.2). CONCLUSIONS: In patients with anemia, tests to ascertain iron status are not appropriately performed in hospitalized patients. Patients found to have iron deficiency anemia who are FOBT-positive undergo endoscopic evaluation more frequently than FOBT-negative patients.

New therapies in hepatitis C virus and chronic liver disease: antifibrotics.

Fibrotic liver disease occurs after any of the various forms of injury to the liver. Fibrosis is a critical factor leading to hepatic dysfunction and portal hypertension and its complications. The fibrogenic cascade is complex but leads to accumulation of extracellular matrix proteins, followed by nodular fibrosis, tissue contraction, and alteration in blood flow. A critical concept emerging is that activation of effector cells, which produce extracellular matrix, underlies the fibrogenic process. The aggregate data has not only helped lead to an understanding of the pathophysiologic basis of hepatic fibrogenesis, but it has also provided an important context with which to base novel antifibrotic therapy.

Prospective comparison of patient experience with colon imaging tests.

PURPOSE: Patient experience varies with the currently available colon imaging tests, including air contrast barium enema, computed tomographic colonography, and colonoscopy. We examined differences in patient experience with colon imaging tests and whether they varied with gender, age, and race. SUBJECTS AND METHODS: Patients with fecal occult blood, hematochezia, iron-deficiency anemia, or a family history of colon cancer underwent air contrast barium enema followed 7 to 14 days later by computed tomographic colonography and colonoscopy. Validated patient experience questionnaires that measured the experience for each test and a separate questionnaire that obtained an overall summary measure were administered after testing. Eleven patient experiences including pain, embarrassment, difficulty with bowel preparation, and satisfaction with tests were examined. RESULTS: A total of 614 subjects completed all 3 imaging tests. The test most patients were willing to repeat was colonoscopy; it also was reported to be the least painful procedure. Patients were least satisfied with air contrast barium enema, and fewer would undergo air contrast barium enema compared with computed tomographic colonography or colonoscopy. There were limited racial and gender differences in perceptions of the tests. Younger adults perceived air contrast barium enema to be more painful than older adults. CONCLUSION: Taking into account a wide variety of patient experience measures, patients preferred colonoscopy to air contrast barium enema and computed tomographic colonography. This finding has important implications for physicians considering different colon imaging tests.

Comparison of radiologists and technologists in the performance of air-contrast barium enemas.

OBJECTIVE: The purpose of this study was to determine whether the rate of polyp detection and the quality of air-contrast barium enema (ACBE) procedures performed by technologists differ from those performed by radiologists. CONCLUSION: Our results showed that well-trained certified technologists can perform ACBE similar in overall quality and accuracy to ACBE performed by attending physicians and residents. Training technologists to perform ACBE may help to alleviate the radiology staffing shortage in the United States.

Causes of errors in polyp detection at air-contrast barium enema examination.

PURPOSE: To retrospectively determine the cause of errors in air-contrast barium enema (ACBE) examination for detection of polyps 6 mm or larger. MATERIALS AND METHODS: The study had institutional review board approval. Informed consent was waived for this HIPAA-compliant study. ABCE findings in 41 subjects with 56 missed polyps were evaluated by two radiologists to determine if the cause of errors was perceptual or technical. A comparison was made between total number of polyps in the proximal and distal colon and those missed at each location (Fisher exact test). The 288 ACBE examinations were assessed on a scale of 0-4 (0, excellent; 4, very poor) for six colonic segments (paired t test). RESULTS: Of 17 polyps 1 cm or larger not detected in 15 subjects, 11 (65%) were missed because of technical errors and six (35%) because of perceptual errors. Eight (72%) technical and four (67%) perceptual errors occurred proximal to the splenic flexure. One 3.5-cm cecal carcinoma was not diagnosed prospectively (perceptual error). Of 39 6-9-mm polyps not detected in 26 subjects, 35 (90%) were missed because of technical errors and four (10%) because of perceptual errors. Eighty percent of technical and 75% of perceptual errors were in the proximal colon. When the proportion of polyps in the proximal and distal colon was compared, 22 (63%) of 35 polyps in the distal colon and 15 (26%) of 58 in the proximal colon were detected (P = .0009). There were no detectable differences in the quality of studies in subjects whose polyps were detected and subjects whose polyps were missed (P > .05). CONCLUSION: Technical errors were more common than perceptual errors. The majority of missed polyps were in the proximal colon. Detection rates of polypoid lesions might increase if the quality of ACBE examination can be improved, especially in the proximal colon.

Occult gastrointestinal bleeding.

Occult gastrointestinal bleeding commonly manifests as iron deficiency anemia or fecal occult blood. Iron deficiency anemia results from chronic occult gastrointestinal bleeding. Evaluation of asymptomatic patients who have iron deficiency anemia or fecal occult blood usually should begin with investigation of the colon. Colonoscopy is preferred, but flexible sigmoidoscopy plus air contrast barium enema, or computed tomographic colonography may be acceptable in certain circumstances. If evaluation of the colon does not reveal a bleeding site, evaluation of the upper gastrointestinal tract is mandatory in patients who have iron deficiency anemia, and this should be considered in those who have fecal occult blood. In patients who have gastrointestinal symptoms, evaluation of the portion of the gastrointestinal tract from which the symptoms is derived should be pursued initially. The role of small intestinal investigation is controversial, and this probably should be reserved for patients who have iron deficiency anemia and persistent gastrointestinal symptoms or those who fail to respond to appropriate therapy. Celiac sprue should be considered as a potential cause of iron deficiency anemia in all patients. The treatment and prognosis of patients who have iron deficiency anemia or fecal occult blood depends on the gastrointestinal tract abnormality(ies) identified. Those without identifiable bleeding sites generally respond to conservative management and have a favorable prognosis. On the other hand, the outlook is poorer for patients with refractory occult blood loss or those who have vascular ectasias. Both groups of patients are clinically challenging and require a focused and experienced team approach to diagnosis and therapy.

Prospective comparison of air-contrast barium enema and colonoscopy in patients with fecal occult blood: a pilot study.

BACKGROUND: The utility of air-contrast barium enema and colonoscopy for evaluation of the colon has been debated. Air-contrast barium enema is less expensive and invasive than colonoscopy, but it also is less sensitive and specific. Further, although air-contrast barium enema may be less painful than colonoscopy, it often is poorly tolerated by patients. Thus, this study compared the sensitivity and the specificity of air-contrast barium enema and colonoscopy for detection of colonic lesions in patients with fecal occult blood. METHODS: Over a 30-month period, patients with fecal occult blood were recruited. Patients underwent standard air-contrast barium enema, followed by colonoscopy 7 to 14 days later. Colonoscopists were blinded to the results of air-contrast barium enema until the colonoscopy was completed, after which the results were disclosed. If the findings were discrepant, colonoscopy was repeated. RESULTS: A total of 100 patients were evaluated. Nine air-contrast barium enemas were reported to be inadequate, and the cecum was not intubated at colonoscopy in two patients. In the remaining patients, 5 cancers were identified (1 each cecum, transverse colon, descending colon, sigmoid colon, and rectum) by both studies. Sixty-six polypoid lesions were identified in 30 patients. Diverticula were identified in 42 patients by air-contrast barium enema and in 18 patients by colonoscopy. Air-contrast barium enema detected 3 of 36 polypoid lesions 5 mm or less in diameter, 5 of 15 adenomas 6 to 9 mm in size, and 4 of 15 adenomas 10 mm or greater in diameter (sensitivity 8%, 33%, and 27%, respectively). After excluding patients with diverticula, air-contrast barium enema detected 3 of 7 adenomas 10 mm or greater in size. Overall, 12 polypoid lesions or filling defects were identified by air-contrast barium enema that could not be verified by colonoscopy. The specificity of air-contrast barium enema for lesions 1.0 cm or greater in size was 100%; for those 6 mm or greater, it was 97%. CONCLUSIONS: Air-contrast barium enema accurately detects colon cancer and diverticula. Its sensitivity for detection of polypoid lesions or adenomas is poor and was confounded by the presence of diverticula.