Skin Deep: A Rare Case of Thyrotoxic Periodic Paralysis in an African American Patient

Background: Thyrotoxic Periodic Paralysis (PP) is a rare form of hypokalemic PP that occurs in association with hyperthyroidism, especially Grave’s disease. This disease is frequently seen in males and is particularly prevalent among Asians with an incidence rate of 2%. In non-Asian populations, the incidence among those with hyperthyroidism is even lower at 0.1 - 0.2% and therefore significantly rare in African populations. Inability to recognize this emergency in the non-Asian population can therefore result in potentially fatal outcomes. Case Presentation: A 27 year old African American male with a history of Grave’s disease presented to the emergency department (ED) with the inability to move his muscles. Patient was initially diagnosed with Grave’s disease in 2017 when he was found to have suppressed TSH with elevated TSI and started on methimazole 40mg daily. The patient ran out of methimazole about 2 weeks prior to presentation and woke up on the day of admission with extreme muscle weakness. At the outside hospital, he was found to have potassium of 1.5mEq/L,TSH of < 0.1uL/ml and Free T4 of 3.4 ng/dL. He was given 1000 mg Propylthiouracil, stress dose hydrocortisone, propranolol and potassium replacement and then transferred to our ED for Endocrine evaluation. On assessment, he complained of nausea, vomiting, full body muscle weakness, tingling in his extremities and irritability. He denied any recent illnesses. On physical exam, Temperature 97.4 F, Respiration 18, Pulse 84, BP 157/72, O2 saturation 99%. His thyroid gland was enlarged however non-tender and without bruit. He had normal respiratory and cardiac exam. He was lying flat in bed and unable to raise his limbs against gravity and also unable to hold up his limbs when raised. He lacked his patellar and ankle jerk reflexes bilaterally. He was otherwise alert and oriented x 3. On labs, TSH was 0.004 uL/ml, Total T3 was 294 ng/dL, Free T4 of 3.01 ng/dL, Potassium was 2.1 mEq/L. His potassium was cautiously replaced and improved to 4.7 mEq/L later in the day, at which time, the patient was able move and sit up in bed. He was restarted on Methimazole 40mg daily for his thyroid disease and arranged for outpatient follow up. Discussion: Thyrotoxic PP is seen in a male-to-female ratio ranging from 17:1 to 70:1 and occurs at an average age of 20-40 years. Thyrotoxic PP is especially rare in the non-Asian population at an incidence rate of 0.1 - 0.2%. Nevertheless, in setting of ever-growing diversity due to immigration and inter-race relationships, it is difficult to predict one’s genetics based on the color of their skin. It is possible that our African American patient may have an Asian ancestor unbeknownst to him. Therefore, we must keep a broad differential regardless of one’s race so as to not miss timely diagnosis of medical emergencies which can result in reduced muscle strength, flaccid paralysis, respiratory failure, cardiac arrhythmias and eventual death.

Case Report of Acute Liver Failure Induced By Isotretinoin Medication

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.

Case Report of Acute Liver Failure Induced By Isotretinoin Medication

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.

A phase II trial of cabozantinib and erlotinib for patients with EGFR and c-Met co-expressing metastatic pancreatic adenocarcinoma (PDAC).

e16764 Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .

SAT-474 Amiodarone-Induced Thyrotoxicosis After Weight Loss Following Sleeve Gastrectomy

AMIODARONE-INDUCED THYROTOXICOSIS AFTER WEIGHT LOSS FOLLOWING SLEEVE GASTRECTOMY INTRODUCTION: Bariatric surgeries have shown major health benefits improvement in co-morbidities such as HTN and DM. We are less familiar with how these surgeries affect the pharmacokinetics of drugs.1,2 CLINICAL CASE: Our patient is a 65-year-old man with a fib/v tach and no prior thyroid history. He was on amiodarone 200 mg daily since September 2016. He had sleeve gastrectomy in March 2019 at weight 380 lbs. By June 2019, weight was 278 lbs. In June 2019, he had palpitations, diarrhea, and heat intolerance for one month. Labs showed: TSH <0.01 (0.4 – 4.5 MCIU/L), FT4 6.5 (0.8 – 1.8 NG/DL), and TT3 309 (76 – 181 NG/DL). Other labs: TPO antibodies <1 IU/mL (<9 IU/mL) TSI <89 (<140% baseline). Thyroid sonogram was heterogeneous without nodule He started Methimazole (MMI) 20mg BID and Prednisone 40mg daily. In the next seven weeks, symptoms and TFTs improved. FT4 was 3.1 NG/DL, TT3 was 85 NG/DL, but TSH remained <0.01 MCIU/L. Because of the rapid improvement, he was felt to have type 2 AIT (destructive thyroiditis). MMI was quickly tapered. Prednisone was tapered to 30mg daily. At week 8, he was hospitalized for septic shock from diverticulitis and perianal abscess. He also had leukopenia attributed to MMI and sepsis. MMI was stopped. Amiodarone was stopped by cardiology. TFTs during hospitalization improved on only steroids: TSH was 0.01 MCIU/ML, FT4 was 2.34 NG/DL, and TT3 was 0.56 NG/ML. He was discharged on Prednisone 30mg daily with plans to taper off steroids. CONCLUSION: Our patient is the second reported case of AIT after bariatric surgery-induced weight loss. Amiodarone is a highly lipophilic drug that accumulates in adipose tissue. Rapid weight loss may result in the release of large amounts of amiodarone into the circulation with resultant thyrotoxicosis. As clinicians, we should be aware that patients who undergo bariatric surgery are at risk for complications that are not only directly related to the operation but also related to rapid weight loss that affects how the body handles drugs. REFERENCES 1. Bourron O, Ciangura C, Bouillot J-L, Massias L, Poitou C, Oppert J-M. Amiodarone-induced hyperthyroidism during massive weight loss following gastric bypass. Obes Surg. 2007;17(11):1525–1528. http://www.ncbi.nlm.nih.gov/pubmed/18219784. Accessed September 21, 2019. 2. Geraldo M de SP, Fonseca FLA, Gouveia MR de FV, Feder D. The use of drugs in patients who have undergone bariatric surgery. Int J Gen Med. 2014;7:219–224. doi:10.2147/IJGM.S55332

P150 Risk of hepatitis flare in patients with previous hepatitis B virus exposure amongst inflammatory bowel disease patients: results from a territory-wide Hong Kong IBD Registry study

Background Biological therapies, thiopurines and steroid are commonly used in the treatment of inflammatory bowel disease (IBD) and may cause hepatitis B virus (HBV) reactivation. However, their exact risk of hepatitis B flare in patients with previous HBV exposure is poorly defined. We aim to study the risk of hepatitis flare in IBD patients with previous HBV exposure. Methods Patients were identified from a territory-wide Hong Kong IBD Registry. IBD patients who were negative for HBsAg and received biological therapies or thiopurines or steroids from 1 January 2000 to 30 June 2019 were included. Patients who were positive for total antibody to hepatitis B core antigen (anti-HBc) and/or hepatitis B surface antigen (anti-HBs) were defined to have previous HBV exposure. Primary endpoint was development of hepatitis flare (alanine Aminotransferase [ALT) >80U/L). Results Total 369 patients fulfilled the inclusion criteria and were classified into three groups: anti-HBs positive only (n = 246); anti-HBs and anti-HBc positive (n = 78) and anti-HBc positive only (n = 45). Median follow-up duration was 60 months (Interquartile range: 32.7–60 months). Seventy-six IBD patients (20.6%) developed hepatitis flare. Cumulative incidence of hepatitis flare were 13.2%, 18.3% and 22% at 12 months, 36 months and 60 months respectively. Use of thiopurine [adjusted hazard ratio (aHR) 2.56; 95% Confidence Interval (CI) 1.54 – 4.26, p < 0.001]and ever exposure to steroid [aHR 2.73; 95% CI 1.30–5.72; p = 0.008] were risk factors for hepatitis flare after adjustment of baseline ALT level. The use of biological therapy was not associated with risk of hepatitis flare [aHR 1.79; 95% CI 0.79–3.99; p = 0.14]. Ever exposure to steroid was associated with increased risk of hepatitis flare irrespective of the peak dose (<20mg prednisolone daily, 20-40mg daily or >40mg daily) [aHR: 2.34–4.18]. Fifteen patients (4.1%) developed severe icteric hepatitis flare (ALT > 120U/L and bilirubin >38 mmol/L). Cumulative incidence of severe icteric hepatitis flare were 2.7%, 7.2% and 8.4% at 12 months, 36 months and 60 months respectively. Conclusion Amongst IBD patients with previous HBV exposure who were treated with biological therapy, thiopurines or steroid, 20.6% developed hepatitis flare. The use of thiopurine and ever exposure to steroid were risk factors for hepatitis flare. The use of biological therapy was not associated with risk of hepatitis flare.

A single-institution experience with the hyper-CVAD regimen in aggressive NHL.

e18510 Background: Hyper-CVAD (± rituximab) is a chemotherapy regimen designed as a treatment for aggressive hematological malignancies. It consists of 8 cycles. Cycle 1, 3, 5, 7 (3-4 weeks/cycle) includes cyclophosphamide 300mg/m2 IV over 2 hours (hrs) every 12 hrs for 6 doses on day 1-3 + Mesna 600mg/m2 per day continuous IV on days 1-3 to start 1 hr before cyclophosphamide till 12 hrs after completion of cyclophosphamide + vincristine 2mg IV on days 4 and 11 + doxorubicin 50mg/m2 IV over 24 hrs on Day 4 + dexamethasone 40mg daily orally on days 1-4 and days 11-14. Cycle 2, 4, 6, 8 (3-4 weeks/cycle) consist of high dose methotrexate (MTX) (200mg/m2) IV over 2 hrs followed by 800mg/m2 continuous IV infusion over 22 hrs on day 1 + cytarabine 3gm/m2 (1gm/m2 for patient age over 60 years old) IV over 2 hrs every 12 hrs for doses on days 2 and 3 + leucovorin 50mg IV every 6 hrs starting 12 hrs after completion of MTX till MTX level < 0.05µM. Hyper-CVAD is a short intensified regimen given over eight months compared to known therapy for ALL and Burkitt lymphoma. Methods: Retrospective review of all cases of acute lymphoblastic leukemia/lymphoma and Burkitt’s lymphoma between 2000 and 2012 was done. It included all patients and evaluated response to therapy including Hyper-CVAD. Results: A total of 79 patients with aggressive acute lymphoblastic leukemia/lymphoma and Burkitt’s NHL were analyzed. Mean age 39 years (range 15-75 years). All patients were admitted at least twice with febrile neutropenia. Prolonged cytopenias were observed in more than 50% of patients. Conclusions: Hyper-CVAD is an intense regimen that produces high rates of clinical remission in less than 8 months of therapy compared to established regimen for aggressive hematological malignancies. [Table: see text]

Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to <5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.

Antimicrobial Effectiveness of Chlorhexidine Chewing Gums on Streptococcus Mutans Counts– An in vivo Microbiological Study

The aim of the present study was to evaluate the antimicrobial efficacy of Chlorhexidine chewing gums and to assess the effect of dosage and frequency of intake of Chlorhexidine gums on Streptococcus mutans(SM)count. Method: The sample consisted of 30 subjects, divided into two groups AI & AII. Each group consisted of 15 subjects. Group AI chewed 2 Chlorhexidine Chewing gum X Twice Daily for 20 minutes (Total = 4 gums Daily) & Group AII chewed 2 Chlorhexidine Chewing gum X Four times daily for 20 minutes (Total= 8 gums Daily) & saliva sample was collected & agar plates were inoculated for SM colony count. The study was carried for a week's time and salivary sample collected were Baseline, Day 1 morning and evening, Day 4 evening, Day7 morning and evening. Results: After the gum was chewed, it was observed that the colony count started to decrease when compared with baseline in both the groups. The fall in SM count was statistically highly significant with p &lt; 0.001 in both the groups. When comparing between Group AI (Dosage 20mg daily) and Group AII (Dosage 40mg daily), the fall in SM count for both the groups was not statistically significant with p-value &gt; 0.05. It was concluded that there was reduction in the level of Salivary SM, but was not statistically significant, by increasing the dosage and frequency of intake of Chlorhexidine containing gums. Conclusions: We recommend that dosage of Chlorhexidine containing chewing gums can be restricted to four gums instead of eight gums per day.