BACKGROUND:The trace element zinc is essential for multiple biological processes and analyzed in suspected cases of deficiency or toxicity. A systematic approach to abnormal results will aid the diagnosis of a patient with low or high zinc concentration in plasma in a more clinically efficient and cost-effective manner. CONTENT:True zinc deficiency can be attributed to both acquired and inherited causes; however, falsely low concentrations may be obtained through sample timing, during inflammatory states, and in the presence of certain medications and hypoalbuminemia. High concentrations of zinc may be due to fasting, hemolysis, or environmental contamination of blood test tubes. The clinical status and condition of the patient should be considered to allow a targeted investigation to be carried out. SUMMARY:Diagnostic flow charts have been created to help aid healthcare professionals to investigate the cause of both low and high zinc concentrations where the cause is not immediately apparent. This article provides a set of algorithms to suggest an investigative strategy in cases of unexpected abnormalities in plasma zinc.

BackgroundGrossly lipaemic samples are a significant cause of analytical errors, potentially impacting patient care. The causes of lipaemia are varied and often unavoidable, while methods to reduce lipaemia through gold-standard ultracentrifugation are limited by availability, transportation and cost. Benchtop centrifugation has been proposed as an alternative method to reduce lipaemia.MethodsFifty-three grossly lipaemic serum samples (lipaemia >201.8 mg/dL) that were unsuitable for analysis were selected and centrifugated at 18840 g for different time-periods with lipaemia measured prior to and after centrifugation. Core analytes were measured on serum samples free of lipaemia before and after 30 min of centrifugation at 18840 g to assess the effect of the centrifugation process.ResultsAfter centrifugation for 5 min, 90% of grossly lipaemic samples were either ideal (lipaemia <50 mg/dL) or adequate (lipaemia 50.1-201.7 mg/dL) for analyte testing. All samples were either adequate or ideal for testing following centrifugation for 30 min. Although some analytes showed a statistically significant change in the measured concentration post high-speed centrifugation, none had clinically significant changes according to analyte specific reference change value (RCV) analysis. Aspartate aminotransferase (AST) and creatine kinase (CK) demonstrated the most notable reductions in activity, but these did not exceed their RCV.ConclusionsBenchtop centrifugation shows potential laboratory utility in reducing lipaemia whilst maintaining clinically reliable results, however small sample sizes preclude firm conclusions. Further research is warranted to increase the sample size with finer time-point tuning, sub-group analysis and temperature analysis, due to the potential for sample heat injury, to balance practicality and accuracy.

Ferritin measurement is a common laboratory test in dermatology. Ferritin is a marker of iron storage in the human body but can also be -elevated in inflammatory states. Therefore, changes in ferritin are nonspecific, and correlation of specific clinical findings and risk factors with ferritin concentration and other biomarkers, e.g. iron studies or C-reactive protein tests, is recommended. This article discusses iron metabolism and the indications for ferritin measurement in dermatology and how to interpret the laboratory results.

Background and Objective: The following article is part of a special series to aid the reader in diagnosing the cause of various electrolyte imbalances. By the end of the article, the reader should be able to order and interpret appropriate laboratory investigations when faced with a patient with hypercalcaemia or hypocalcaemia. Methods: A narrative, focused literature review was performed using Medline, PubMed, Google Scholar and OMIM during August 2023 to November 2023 to identify references published from database inception. Reference lists from these articles, as well as expert opinion from the authors, were also used. Language was restricted to English. Key Content and Findings: Calcium is an essential electrolyte and its blood concentration is tightly controlled by multiple homeostatic hormones, including parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D. However, calcium imbalance can occur in many disease states and can lead to significant morbidity and mortality. PTH analysis is of primary importance in identifying the cause of a calcium disturbance. It should be noted that calcium results are particularly susceptible to being falsely low or high depending on whether ionised or total calcium is analysed, therefore the validity of calcium results should always be questioned if the results are not consistent with the clinical presentation. Hypercalcaemia is most commonly associated with primary hyperparathyroidism (PHPT) or malignancy. Hypocalcaemia is much rarer than hypercalcaemia, and if no obvious cause is found-e.g., post total thyroidectomy-consider hypomagnesaemia. Conclusions: Diagnostic flow charts are presented, and the limitations of the laboratory tests discussed. These algorithms, by focusing on the approach to the investigation of hypercalcaemia and hypocalcaemia, should support healthcare professionals to efficiently and rapidly diagnose the majority of causes of abnormal calcium states.

Background and Objective: The following article is part of a special series to aid the reader in diagnosing unexpected abnormal test values. The panel of liver tests can vary in content but usually contains a transaminase activity, however, transaminases can be found in many other tissues and affected by a wide range of non-liver processes. The objective is to review the causes of low or high transaminase activity in human serum so that the reader will be able to order and interpret appropriate investigations when faced with a patient with unexpected abnormal transaminases. A detailed discussion of neonatal causes will be excluded.

Background and Objective: The following article is part of a special series to aid the physician in diagnosing the cause of various plasma abnormalities. Patients presenting with low or high alkaline phosphatase (ALP) activity can present a diagnostic challenge, particularly in the absence of symptoms. The objective is to provide information and algorithms to support the physician to order and interpret appropriate investigations when faced with this situation. Methods: A narrative, focused literature review was performed of English language resources using PubMed, OMIM, ScienceDirect, and Google. References published from database inception to June 2023 were searched for from February 2023 to June 2023. Further articles were identified from reference lists. Key Content and Findings: Bone and liver are the primary sources of ALP activity. When activity is low correlates with potassium, magnesium, and calcium concentrations which can help rule out specimen contamination and identify bone disease and malnutrition. When activity is high correlates with liver function tests, followed by a bone profile if normal. Analytical limitations include the range of isoforms present such as macro-ALP which can affect the results obtained. Conclusions: Diagnostic algorithms are presented that should support healthcare professionals to efficiently and systematically approach people with these abnormalities.

Diagnostic errors affect patient management, and as blood gas analysis is mainly performed without the laboratory, users must be aware of the potential pitfalls. The aim was to provide a summary of common issues users should be aware of.A narrative review was performed using online databases such as PubMed, Google Scholar and reference lists of identified papers. Language was limited to English.Errors can be pre-analytical, analytical or post-analytical. Samples should be analysed within 15 min and kept at room temperature and taken at least 15-30 min after changes to inspired oxygen and ventilator settings, for accurate oxygen measurement. Plastic syringes are more oxygen permeable if chilled. Currently, analysers run arterial, venous, capillary and intraosseous samples, but variations in reference intervals may not be appreciated or reported. Analytical issues can arise from interference secondary to drugs, such as spurious hyperchloraemia with salicylate and hyperlactataemia with ethylene glycol, or pathology, such as spurious hypoxaemia with leucocytosis and alkalosis in hypoalbuminaemia. Interpretation is complicated by result adjustment, for example, temperature (alpha-stat adjustment may overestimate partial pressure of carbon dioxide (pCO2) in hypothermia, for example), and inappropriate reference intervals, for example, in pregnancy bicarbonate, and pCO2 ranges should be lowered.Lack of appreciation for patient-specific and circumstance-specific reference intervals, including extremes of age and altitude, and transformation of measurements to standard conditions can lead to inappropriate assumptions. It is vitally important for users to optimise specimen collection, appreciate the analytical methods and understand when reference intervals are applicable to their specimen type, clinical question or patient.

Background and Objective: The following article is part of a special series to aid the reader in diagnosing the cause of various plasma derangements in humans. By the end of the article, the reader will be able to order and interpret appropriate investigations when faced with a patient with low or high lactate dehydrogenase (LDH) activity in plasma. Methods: A narrative, focused literature review was performed using Medline, OMIM and Google Scholar from April 2023 to September 2023 to identify references published from database inception to September 2023; reference lists from these articles were also used. The language was restricted to English. Key Content and Findings: LDH is produced by all cells and can be released into plasma in a vast number of pathological processes. Liver and red blood cells are a common source as is skin, lung, muscle, and the gastrointestinal tract. A laboratory approach to the investigation of elevated LDH is presented, no algorithm was produced for low LDH activity as causes are too scarce and of unlikely clinical significance. The clinical status and condition of the patient should be considered first in order to carry out a targeted investigation however full blood count, liver and renal function tests may be used as first line tests. Conclusions: Diagnostic flow charts have been created to help aid healthcare professionals to investigate the cause of elevated LDH activity where the cause is not immediately apparent. These algorithms have been presented and created within the limitations of the laboratory tests discussed within the paper, selected to be widely available.

Bedbugs are on the rise in urban populations across the world, perhaps reflecting the ban on the use of organophosphates in many countries worldwide. They are flat obligate haematophagous insects, preferring humans, and as a consequence the bedbug bites lack toxins and can often go unnoticed for some time. Bites can, however, cause weals, purpura, petechiae, vesicles, pustules, papular urticaria, localized infection and rarely anaphylaxis. Infestations have to be confirmed by finding the bugs, usually around the bed of the person being bitten. Eradication usually requires a combination of physical (for example high temperature, mattresses protectors, traps, cold) and chemical methods (for example chrysanthemic acid derivatives plus potentiators such as geraniol and piperonyl butoxide or acetylcholine esterase inhibitors).

Biochemical confirmation of a diagnosis of hypercortisolism (Cushing syndrome) is vital to direct further investigations, especially given the overlap with non-autonomous conditions, such as pseudo-Cushing, and the morbidity associated with missed diagnoses. A limited narrative review was performed focusing on the laboratory perspective of the pitfalls of making a biochemical diagnosis of hypercortisolism in those presenting with presumed Cushing syndrome. Although analytically less specific, immunoassays remain cheap, quick, and reliable in most situations. Understanding cortisol metabolism can help with patient preparation, specimen selection (e.g., consideration of urine or saliva for those with possible elevations of cortisol binding globulin concentration), and method selection (e.g., mass spectrometry if there is a high risk of abnormal metabolites). Although more specific methods may be less sensitive, this can be managed. The reduction in cost and increasing ease of use makes techniques such as urine steroid profiles and salivary cortisone of interest in future pathway development. In conclusion, the limitations of current assays, particularly if well understood, do not impede diagnosis in most cases. However, in complex or borderline cases, there are other techniques to consider to aid in the confirmation of hypercortisolism.

Buss and colleagues highlight the risks of undertaking multiple tests with reference intervals that incorporate 95% of a healthy population.1 Further limitations include the relevance for that person—for example, taking into account age and sex for albumin and haematological parameters.2 3 Different time of day intervals are required for analytes that showdiurnal variation, suchas cortisol, testosterone, prolactin, and iron, or standardisation of the sampling time. The applicability to an individual of a general population reference interval is controversial.4 Results in the reference interval may not exclude disorders and comorbidities can affect interpretation—for example, vitamin D is a negative acute phase protein.1 5

The renaming of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis is timely and important.1 The most powerful figure from the Delphi consensus statement, Fig. 6, neatly summarises how to approach the new classification.1 There are some interesting points in the cardiometabolic risk factor section that may however lead to confusion.

This is a summary article of a noteworthy publication that has reclassified nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), respectively. A new term, MASLD with increased alcohol intake (MetALD), has been proposed to classify patients previously classified as having NAFLD with excess alcohol intake. This article is designed to draw the reader’s attention to the changes in nomenclature in liver disease. This is pertinent in dermatology as many patients copresent with MASLD.

To the Editor: We read with interest the report by Franciosi et al1Franciosi A.N. Ralph J. O'Farrell N.J. et al.Alpha-1 antitrypsin deficiency–associated panniculitis.J Am Acad Dermatol. 2021; Abstract Full Text Full Text PDF Scopus (4) Google Scholar on alpha-1 antitrypsin deficiency (AATD)–associated panniculitis. We add 3 comments to their work and highlight its importance. First, Franciosi et al1Franciosi A.N. Ralph J. O'Farrell N.J. et al.Alpha-1 antitrypsin deficiency–associated panniculitis.J Am Acad Dermatol. 2021; Abstract Full Text Full Text PDF Scopus (4) Google Scholar identified pulmonary and hepatic pathology in approximately 30% and 10% of cases, respectively. Concomitant AATD-associated disease can suggest AATD as a potential cause of panniculitis. However, the likelihood of observing this will be strongly influenced by the age of presentation and smoking status. Franciosi et al1Franciosi A.N. Ralph J. O'Farrell N.J. et al.Alpha-1 antitrypsin deficiency–associated panniculitis.J Am Acad Dermatol. 2021; Abstract Full Text Full Text PDF Scopus (4) Google Scholar showed the age of presentation to be highly variable in AATD-associated panniculitis (range, 7-85 years; mean, 39.1 years [standard deviation, 16.8]). A Swedish prospective cohort study following more than 100 individuals with AATD since birth provides further information. Liver disease affected 17% of PiZZ/PiZnull individuals before the age of 6 months but most survived,2Mostafavi B. Piitulainen E. Tanash H.A. Survival in the Swedish cohort with alpha-1-antitrypsin deficiency, up to the age of 43-45 years.Int J Chron Obstruct Pulmon Dis. 2019; 14: 525-530Crossref PubMed Scopus (12) Google Scholar and was not observed in adults up to 40 years of follow-up, with the exception of 2 cases associated with alcohol consumption, suggesting that adult-onset AATD-associated liver disease has a later age of onset in most cases.2Mostafavi B. Piitulainen E. Tanash H.A. Survival in the Swedish cohort with alpha-1-antitrypsin deficiency, up to the age of 43-45 years.Int J Chron Obstruct Pulmon Dis. 2019; 14: 525-530Crossref PubMed Scopus (12) Google Scholar,3Mostafavi B. Diaz S. Tanash H.A. et al.Liver function in alpha-1-antitrypsin deficient individuals at 37 to 40 years of age.Medicine (Baltimore). 2017; 96: e6180Crossref PubMed Scopus (16) Google Scholar Respiratory symptoms were common in smokers in their twenties, but chronic obstructive pulmonary disease (COPD) was not diagnosed until after 30 years of age, consistent with most cases in the literature.4Piitulainen E. Mostafavi B. Tanash H.A. Health status and lung function in the Swedish alpha 1-antitrypsin deficient cohort, identified by neonatal screening, at the age of 37-40 years.Int J Chron Obstruct Pulmon Dis. 2017; 12: 495-500Crossref PubMed Scopus (26) Google Scholar By the age of 37 to 40 years, most of the small number of smokers with severe AATD (n = 3) had a COPD diagnosis, but there were no cases in nonsmokers.2Mostafavi B. Piitulainen E. Tanash H.A. Survival in the Swedish cohort with alpha-1-antitrypsin deficiency, up to the age of 43-45 years.Int J Chron Obstruct Pulmon Dis. 2019; 14: 525-530Crossref PubMed Scopus (12) Google Scholar Clinical signs of adult-onset liver disease were not observed by this age, excluding 2 cases associated with alcohol overconsumption, suggesting a later age of onset in most cases.2Mostafavi B. Piitulainen E. Tanash H.A. Survival in the Swedish cohort with alpha-1-antitrypsin deficiency, up to the age of 43-45 years.Int J Chron Obstruct Pulmon Dis. 2019; 14: 525-530Crossref PubMed Scopus (12) Google Scholar,3Mostafavi B. Diaz S. Tanash H.A. et al.Liver function in alpha-1-antitrypsin deficient individuals at 37 to 40 years of age.Medicine (Baltimore). 2017; 96: e6180Crossref PubMed Scopus (16) Google Scholar We reviewed the cases identified by Franciosi et al1Franciosi A.N. Ralph J. O'Farrell N.J. et al.Alpha-1 antitrypsin deficiency–associated panniculitis.J Am Acad Dermatol. 2021; Abstract Full Text Full Text PDF Scopus (4) Google Scholar and found consistent results. In the 31 individuals aged less than 30 years, there were 2 cases with known AATD, both identified from earlier hepatitis, and no cases of COPD. A history of hepatitis or neonatal jaundice may thus be the only clue in patients presenting at less than 30 years of age. Clinicians should also be aware that COPD may be misdiagnosed as asthma due to the young age of presentation or that COPD may be present at the time of AATD-associated panniculitis presentation but not yet diagnosed. Respiratory system inquiry at presentation may thus be helpful in adults. Second, a skin biopsy can provide information not only from histological findings, as reviewed by Franciosi et al,1Franciosi A.N. Ralph J. O'Farrell N.J. et al.Alpha-1 antitrypsin deficiency–associated panniculitis.J Am Acad Dermatol. 2021; Abstract Full Text Full Text PDF Scopus (4) Google Scholar but also from the act of biopsy itself. We identified 2 cases in whom the characteristic oily discharge of AATD-associated panniculitis was first identified during the skin biopsy procedure. Other potential causes for ulcerating/draining panniculitis include pancreatic panniculitis, factitial panniculitis, and infectious panniculitides. Finally, diagnosis can be delayed in AATD-associated panniculitis. We identified more than 20 cases in whom panniculitis lesions were present for at least 3 months prior to the AATD being diagnosed, including reports of recurrent panniculitis episodes for 2 years, 4 years, and 5 years. Diagnosis not only allows instigation of treatment but also offers individuals with severe AATD the possibility of a close-to-normal life expectancy with smoking avoidance.5Tanash H.A. Nilsson P.M. Nilsson J.A. et al.Survival in severe alpha-1-antitrypsin deficiency (PiZZ).Respir Res. 2010; 11: 44Crossref PubMed Scopus (52) Google Scholar This benefit can extend to families if cascade screening is employed. Franciosi et al1Franciosi A.N. Ralph J. O'Farrell N.J. et al.Alpha-1 antitrypsin deficiency–associated panniculitis.J Am Acad Dermatol. 2021; Abstract Full Text Full Text PDF Scopus (4) Google Scholar thus raise awareness of a condition with important implications, and their algorithm for AATD testing may improve case detection and facilitate more prompt diagnosis in future years. None disclosed.