Acute Pancreatitis with Normal Amylase/Lipase Levels? A Rare Case Study in Pakistan, an unusual manifestation of cystic fibrosis

Acute Pancreatitis (AP) is the inflammation and auto-digestion of the pancreas and is usually associated with the elevation of serum amylase and lipase levels. Here, we report a rare presentation of AP with normal pancreatic enzymes and lupus vulgaris (LV) in a patient with cystic fibrosis (CF). The chief complaints included severe abdominal pain in association with fever and vomiting. On examination, the abdomen was tense and tender. There were bilateral coarse crepitations with expiratory wheeze more pronounced on the left lower chest. After detailed clinical evaluation, a provisional diagnosis of acute pancreatitis, with pneumonitis and oral thrush was established. Routine laboratory investigations were performed to confirm the diagnosis. However, the serum amylase and lipase came out within the normal reference range. So, computerized tomography (CT) scan of the abdomen was performed which showed a diffusely swollen and edematous pancreas along with peri-pancreatic stranding, and hence confirmed the diagnosis. Afterward, the patient was managed conservatively and he had an uneventful recovery. The purpose of reporting this case is to promote awareness among fellow healthcare professionals about this rare manifestation of AP and to prevent any missed diagnosis and serious complications. To conclude, cystic fibrosis may have an unusual presentation like AP without pancreatic enzyme elevation which may create a diagnostic dilemma. Hence, in such cases, a strong clinical suspicion and supportive radiological findings play a critical role in the establishment of the diagnosis.

Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA.

A Novel KMT2D mutation in Kabuki syndrome with elevated liver enzymes and congenital bilateral hip dislocation

Kabuki syndrome (KS) is a rare syndrome that involves defects in a wide range of organs, with each organ showing a different severity of symptoms. Two genes have been associated with patients with KS: lysine (K)-specific demethylase 6A (KDM6A) and lysine (K)-specific methyltransferase 2D (KMT2D). The study reported the case of an 18-month-old Turkish boy diagnosed with KS. The patient showed a typical appearance: widely separated eyes, sparse eyebrows, long palpebral fissures, blue sclera, large prominent ears, and micrognathia. The patient was operated on because of bilateral hip dislocation and undescended testicles. He was also followed up by pediatric gastroenterology with asymptomatic liver enzyme elevation (AST- 79 U/L, ALT -68 U/L, ALP -52 U/L). The whole exome sequencing analysis revealed a novel pathogenic c.13285 C>T (p.Gln4429Ter) mutation in the KMT2D gene. The genotype-phenotype correlation of KS was not precisely established. As per our knowledge, there is limited literature which gives information about the hepato-biliary manifestations of KS. Here, we propose that the new mutation of the KMT2D gene may result in the typical facial features of KS with asymptomatic elevated liver enzymes.

Elevated Pancreatic Enzymes in ICU Patients With COVID-19 in Wuhan, China: A Retrospective Study

Background: Pancreatic enzyme elevation has been reported in patients with COVID-19 during the pandemic. However, with the shortage of medical resources and information, several challenges are faced in the examination and treatment of this condition in COVID-19 patients. There is little information on whether such condition is caused by pancreatic injury, and if this is a warning sign of life threatening complications like multiple organ failure in patients. The objective of this study is to explore the relationship between elevated pancreatic enzymes and the underlying risk factors during the management of COVID-19 patients.Method: A total of 55 COVID-19 patients admitted to the intensive care unit (ICU) of Wuhan Jinyintan hospital from January 1 to March 30, 2020 were enrolled in this study. All participants underwent transabdominal ultrasound imaging to assess their pancreas.Results: Out of the 55 patients, three patients had pancreatitis, 29 (52.7%) with elevated pancreatic enzymes, and 23 (41.8%) without. The most common symptoms of patients with COVID-19 were fever and cough. There was no statistical difference in most baseline characteristics except myalgia on admission. Compared with those having normal enzyme levels, patients with elevated pancreatic enzymes had higher rates of mortality (79.3 vs. 52.2%; P = 0.038), and lower rates of discharge (20.7 vs. 47.8%; P = 0.038). Patients with elevated enzymes had higher incidence of mechanical ventilation (P = 0.004) and kidney injury (P = 0.042) than patients without elevated pancreatic enzymes. The results of multivariable logistic analysis showed that the odds ratio were 10.202 (P = 0.002) for mechanical ventilation and 7.673 (P = 0.014) for kidney injury with the elevated enzymes vs. the normal conditions.Conclusions: The findings show that the incidences of pancreatic enzymes elevation are not low in critical COVID-19 patients and only a few of them progressed to acute pancreatitis (AP). Increased pancreatic enzymes levels is associated with poor prognosis in COVID-19 patients. In addition, the kidney injury and oxygenation degradation are associated with the pancreatic enzymes elevation in COVID-19 patients.

Evaluation of Serum Levels of Lactate Dehydrogenase Isoenzymes in COVID- 19 Patients

Background: This study aimed to determine the serum levels of lactate dehydrogenase isoenzymes (LDH1, LDH2, LDH3, LDH4, and LDH5) and their contribution to the total lactate dehydrogenase enzyme elevation observed in COVID-19 patients. Design of study: This study was conducted in collaboration between Al-Nahrain University/College of Medicine/Chemistry and Biochemistry Department and Al- Yarmouk Teaching Hospital, Baghdad, Iraq. The study included 90 patients with confirmed COVID-19 infection: 45 with severe symptoms, and 45 with mild symptoms during the period from February 2021 to June 2021. The different LDH isoenzymes (LDH1, LDH2, LDH3, LDH4, and LDH5) were determined by enzyme-linked immunosorbent assay (ELISA) kits. Results: This study showed high correlation between total lactate dehydrogenase (LDH) enzyme and disease progression and severity in patients with COVID-19. The study also showed significantly higher levels of the lactate dehydrogenase isoenzymes (LDH1, LDH3, and LDH4) in patients with severe symptoms. Conclusion: This study suggests that elevation of serum lactate dehydrogenase (LDH) in patients with COVID-19 may be associated with the release of more than one of LDH isoenzymes into the bloodstream, therefore the use of total LDH as a specific biomarker for lung affectation in patients with COVID-19 is not specific, but the assay of all LDH isoenzymes could give a better understanding of the tissues most affected by the virus.

Pesky Hiccups; May be Risky!

Background: Hiccups are benign and self-limited condition, but attention should be paid to the underlying conditions when persist. There are various causes of persistent hiccups, including metabolic abnormalities, psychogenic disorders, malignancy, nervous system pathology, medications, pulmonary disorders, or gastrointestinal etiologies. It is rarely attributed to cardiac disease. Case Summary: We report a case of intractable hiccups in a 67 y/o male as the initial symptom of coronary heart disease. He presented with a few-week history of hiccups and no other complaints. Echocardiography demonstrated wall motion abnormalities in the left ventricle with severe impairment of systolic function. He was He was admnistered chlorpromazine and anti-ischemic treatment, and a thallium viability study was advised before cardiac catheterization to confirm viable or nonviable myocardium. He refused further evaluation and was discharged with appropriate care. The gentleman was readmitted for heart failure two weeks after discharge due to poor medication adherence. The delay in treatment had affected his chances of survival, and his hiccuping symptoms had recurred and persisted. Finally, he died after two months from the time of diagnosis. Discussion: This case makes highlights the importance of having a high index of suspicion, especially in elderly diabetic patients where benign self-limiting conditions like hiccups can only present symptoms of severe cardiac disease. Cardiac disease should be considered even when the symptoms are only gastrointestinal; simple investigations in the form of changes in electrocardiogram with cardiac enzyme elevation may disclose the cardiac findings, as they did in our case!

Exposure–safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease

Background Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID). Methods Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea). Results Using data from 1403 subjects with IPF treated with 50–150 mg nintedanib BID, a parametric time-to-first-event model for liver enzyme elevations was established. Besides exposure, gender was a significant covariate, with a three–fourfold higher exposure-adjusted risk in females than males. Subsequent analysis of combined data from IPF, SSc-ILD (n = 576) and progressive fibrosing ILD (n = 663) studies suggested a consistent exposure–liver enzyme elevation relationship across studies. No exposure–diarrhea relationship was found using data from the various fibrosing ILDs, but diarrhea risk was dependent on dose administered. Conclusions The positive correlation between exposure and risk of liver enzyme elevations was consistent across nintedanib studies in IPF, SSc-ILD and progressing fibrosing ILDs other than IPF. The effect size does not warrant a priori dose adjustment in patients with altered plasma exposure (excluding hepatic impairment patients, where there are specific labelling recommendations). For diarrhea, dose administered was a better predictor than exposure.

Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy

Background and aims Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management. Methods Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed. Results Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145–324 for immunotoxicity, N = 103; M = 74, 95% CI 59–92 for other causes; ratio of means 0.34, 95% CI 0.19–0.60, p = <0.001) and higher ALT:AST ratio (M = 1.27, 95% CI 0.78–2.06 for immunotoxicity, M = 0.69, 95% CI 0.59–0.80 for other causes, ratio of means 0.54, 95% CI 0.36–0.82, p = 0.004). Immunotoxicity was more often seen in patients with prior CPI exposure (41.2% of immunotoxicity vs 15.9% of patients without, p = 0.01), anti-CTLA-4 –containing ICI treatments (29.4% of immunotoxicity vs 6.8% of patients without, p = <0.001) and other organ immunotoxicity (76.5% of immunotoxicity vs 19.2% of patients without, p = <0.001). Cause for enzyme elevation was established in most patients after non-invasive investigation. Liver biopsy was reserved for four patients with atypical treatment response. Conclusions Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.

A Case-Report of Drug-Induced Mixed Liver Injury Resulting From Cefepime Exposure

A 99-year-old African-American male presented to the hospital with severe sepsis secondary to a urinary tract infection. Upon initial presentation he was tachycardic, hypotensive and had leukocytosis. While he had signs of acute kidney injury, no signs of acute liver injury were present with his alanine transferase (ALT) and amino transferase (AST) levels measuring at 22 and 44 U/L, respectively. During the treatment course the patient began to show signs of clinical improvement. Despite this, his ALT and AST began to increase on day 2 of treatment and reached their peak of 210 and 239 U/L on day 4. Cefepime-induced liver injury was suspected and cefepime was discontinued. Upon cefepime discontinuation, liver enzymes downtrended and gradually returned to normal. No other likely medication causes of liver injury could be identified and alternative medical causes were ruled out. The lack of an alternative cause and the temporal relationship of cefepime use to hepatic dysfunction support the diagnosis of cefepime-induced liver injury. The patient’s Roussel Uclaf Causality Assessment Methods score was 7, indicating this was a possible case of cefepime-induced liver injury, and the Naranjo Nomogram score was 5 indicating this was a probable case of cefepime-induced liver injury. While cefepime-induced liver injury is rare, clinicians should be cognizant of the potential for this adverse effect if liver enzyme elevation is detected during cefepime therapy and other common causes have been ruled out.