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Simple blood test a mortality predictor
Dr Linda Calabresi
  • Clinical Articles

Smartvax

It’s only been around a few years, but this little bit of technology has already received world wide acclaim for its ability to improve the safety of vaccines in the real-world setting. In simple terms, Smartvax is a program practices install into their software system that sends an SMS directly to patients three days after they receive a vaccination. Patients are asked if they experienced an adverse reaction to the vaccine. A straightforward Yes (Y) or No (N) is all that is required. A No reply ends the conversation, but a Yes will trigger a brief questionnaire that examines the nature of the adverse reaction. If the reaction resulted in the need to seek medical attention this is then flagged in the GP’s software inbox as well as with the local health authority. In practical terms this means adverse reactions are tracked in real time and act as an early warning signal that something could be amiss with a vaccine. Smartvax was developed by Perth GP, Dr Alan Leeb and Ian Peters, following a spate of serious and unexpected adverse reactions among young children who received one brand of flu vaccine back in 2010. It was apparent that a better, more time-sensitive system of monitoring side effects to vaccines was needed to ensure the safety of patients. With the widespread use of mobile phones, the day three post vax text has proven a very effective means of tracking reactions, with a high level of acceptance by patients. In a study from one NSW general practice, the response rate to the SMS  text was 85% post-childhood vaccination, and even in the over 65 year age range the response rate was 74%. Smartvax has now been adopted by more than 280 practices around Australia. The technology can also be used as a reminder system to prompt patients when their next vaccine is due. This is such a clever idea and as general practice becomes more and more tech savvy one can envisage a day when Smartvax is a basic requirement for all clinics that provide vaccinations.   >> Access the resource here

By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Gene-directed prescribing coming to general practice

It’s been around for some time now. The idea of checking a person’s genes to guide appropriate prescribing is not new. It is pretty much standard practice when treating many if not most cancers. But pharmacogenomics in general practice? Looking at an individual’s genetic variants to work out the best treatment for their depression, high cholesterol or gout? Yes – it’s coming. As authors of a recently published review in the Australian Journal of General Practice say, all practising clinicians will have had the experience of patients responding differently to medications despite every indication the medication should be effective, based on all the evidence from randomised controlled trials. It is known that certain genes that regulate the absorption, distribution, metabolism and excretion (ADME) of medications are commonly responsible for this difference in response, as these genes can vary between individuals. Researchers have also identified another group of genes that can influence medication responses directly, which, while less common can have important implications for prescribing. “For example, carbamazepine should not be prescribed to patients with certain human leucocyte antigen (HLA) genotypes because of an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis,” the Australian review authors said. Overall, there have been at least 15 genes identified for which testing can be useful and clinically beneficial in guiding prescribing of 30 different medications. How important will this be in general practice? According to this review at least, very. Firstly the likelihood of having a genetic variation that will influence how a person responds to a common medication is incredibly high. “A recent study of 5400 Australians who underwent testing of just four ADME genes showed that 96% had at least one clinically actionable pharmacogenomic variant,” the review authors said. And then the likelihood that a person will be prescribed one of the drugs that we can now predict the response based on genetic testing is also incredibly high. On analysis of PBS data from 2017, the researchers determined that in that year approximately 1.7 million Australians had filled a prescription for at least one the drugs that has the highest level of evidence of clinically relevant gene-medication association. In their review the authors present a number of case studies which demonstrate the usefulness of genetic testing in clinical practice. These include a patient with anxiety and depression who fails to respond to standard treatment leading to a significant deterioration of her condition. Genetic testing of CYP enzymes found the patient had a genetic variation that meant they rapidly metabolised certain antidepressants, but could be prescribed an alternative medication that wasn’t as dependent on the affected enzyme. Another example involved an older Han Chinese man who needed to be prescribed allopurinol for gout. Because this particular ethnicity has a 20% chance of carrying a gene that puts them at risk of developing severe cutaneous adverse reaction to allopurinol, gene testing was done to help ensure this risk was minimised. Similarly, a genetic variation that gives a higher than normal risk of muscle toxicity when taking simvastatin or atorvastatin can be tested for prior to patients being prescribed these medications, and a safer alternative statin offered. Fundamentally this type of testing will lead to more effective, safer prescribing. The problem is of course, pharmacogenomic testing does not attract a Medicare rebate in Australia and the cost is prohibitive for most patients, even though, according to the review authors the costs are decreasing all the time. A panel of common CYP enzymes now costs between $150 and $200. But the authors suggest this situation will have to change. Even on the basis of economics alone, the government needs to consider allowing rebates for at least some pharmacogenomic tests. “A report in 2008 estimated that the widespread implementation of such testing in Australia could yield savings in excess of $1 billion annually by the avoidance of adverse medication reactions alone,” they said. And imagine how much time, money and angst could be saved if doctors could ensure the first antidepressant a patient is prescribed had a high likelihood of having an effect, rather than the current trial and error approach. However while we wait for better reimbursement for this testing, the authors suggest the doctors consider using the tests where appropriate in patients who are prepared to pay. “Responsible doctors can use the tests and evidence that are already available to improve prescribing decisions for their patients,” they conclude.

Reference

Polasek TM, Mina K, Suthers G. Pharmacogenomics in general practice: The time has come. AJGP. 2019 March; 48(3): 100-5. Available from: https://www1.racgp.org.au/ajgp/2019/march/pharmacogenomics-in-general-practice
By Dr Linda Calabresi
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Dr Kym Mina
  • Clinical Articles

Lactose intolerance and genetic testing

A genetic test is now available to assist in the diagnosis of lactose intolerance in both children and adults.

Key points

  • Lactose intolerance affects approximately 75% of the population.
  • Genetic testing can confirm lactose tolerance (also referred to as lactase persistence).
  • The test differentiates between primary lactose intolerance, due to lactase deficiency, and secondary causes of lactose intolerance, due to other more serious conditions that affect the small bowel.
  • The test is not affected by intercurrent illness and can be performed non-invasively on patients of all ages.
The test only needs to be performed once during a person’s lifetime.

How does the test work?

Testing is now available to detect the genetic variant (LCT-13910C>T) that accounts for close to 100% of lactase persistence in Europeans. Three other genetic variants that have a similar effect and are more common in non-European populations are also detected. These variants are thought to act as enhancers of the lactase gene that in turn stimulates lactase production. When one of these variants is found, a diagnosis of primary lactose intolerance can be excluded. Lactose intolerance can be secondary to other conditions that affect the small bowel, such as gastroenteritis, inflammatory bowel disease and coeliac disease. Genotyping can help to distinguish these causes of intolerance.

What causes lactose intolerance?

Lactose is the major carbohydrate in mammalian milk. Lactose intolerance is caused by deficiency of lactase, the enzyme required for digestion of lactose. Symptoms include abdominal pain, diarrhoea, nausea, flatulence and/or bloating, following the consumption of lactose-containing foods.

Who is affected by lactose intolerance?

After infancy, approximately 75% of the population lose the ability to digest lactose, due to a deficiency in lactase, referred to as primary lactose intolerance. The remainder of people maintain their tolerance for lactose-containing foods because of genetic variants that enable continued production of lactase, referred to as lactase persistence. The prevalence of primary lactose intolerance varies significantly with ethnic background. Lactose intolerance is uncommon in populations that consume large amounts of dairy, for example, northern Europeans (as low as 10%), but is frequent in other populations (as high as 100% in Asiatic countries). It is hypothesised that this is the result of selective genetic advantage; populations that have historically been dependent on dairy food sources for nutrition have survived by having genetic variants that allow tolerance for lactose.

Other testing alternatives

Currently, testing for lactose intolerance can also be performed by a hydrogen breath test with lactose load, or by measurement of intestinal lactase enzyme activity in a biopsy obtained during endoscopy. These tests may give a false-positive result when lactase levels have been affected by a recent viral illness or coeliac disease. These procedures are also not suitable for testing children younger than seven years old. Genotyping is not affected by intercurrent illness and can be performed non-invasively on patients of all ages.

Genetic testing limitations

Please note that genotyping will not identify very rare genetic variants associated with persisting lactase activity, and therefore the absence of a variant can only be used to support a diagnosis of lactose intolerance along with other clinical and laboratory findings.

Arranging a test

  1. Complete a standard pathology request form to refer the patient for ‘lactase persistence’ or ‘lactose intolerance genetic testing’.
  2. Collect or send the patient to a pathology collection centre for a blood test or buccal swab. No special preparation or booking is necessary.
  3. The result is reported back to the doctor, usually within five business days of the laboratory receiving the patient’s sample.

Cost

Medicare does not cover the cost of this test and the patient will receive an invoice for $75.*

References

  • Bayless T, Brown E, Paige DM. Lactase non-persistence and lactose intolerance. Curr Gastroenterol Rep. 2017 May; 19(5): 23. DOI: 10.1007/s11894-017-0558-9
  • Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clin Exp Gastroenterol. 2012; 5: 113-21. DOI: 10.2147/CEG.S32368
  • Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet. 2007 Jan; 39(1): 31-40. DOI: 10.1038/ng1946
  • Heyman MB, Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep; 118(3): 1279-86. DOI: 10.1542/peds.2006-1721
*Correct at time of printing. Please to refer to the Sonic Genetics website, www.sonicgenetics.com.au, for current pricing. General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.
By Dr Kym Mina
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Prof Alan Pearce
  • Clinical Articles

One in 10 patients have ongoing concussion symptoms

Concussion is a temporary disturbance in brain function following an impact to the head. It can also occur after a blow to the body, if the force is transmitted to the head. Most people associate concussion with sports but they can occur anywhere, even at work or school. There are many signs and symptoms of concussion, which may present differently between individuals. These include headaches, nausea, vomiting, slurred speech, dizziness, temporary loss of memory, and inability to focus. Loss of consciousness only occurs in around 10% of concussions. Most people with concussions recover relatively quickly. Around 90% will recover within several days to a couple of weeks. But sometimes symptoms continue beyond a couple of weeks. When symptoms persist beyond three months, the person may be diagnosed as having persistent post-concussion symptoms.

Rest is not always best

We don’t know exactly how common concussions are, because they’re under-reported. Some people don’t think they are a serious injury, so don’t seek treatment, while others mask their injury because they don’t want to be seen as weak. The World Health Organisation classifies concussion, which is a type of traumatic brain injury, as a critical public health issue. Complete physical and mental rest used to be recommended after a concussion. Since 2017, however, the concussion treatment guidelines have evolved to reflect the science. While rest in the immediate 24-48 hours after a concussion is still advised, patients are now encouraged to undertake low-intensity exercise (such as walking, light jogging, or stationary cycling) and light mental stimulation (such as work or study) over the following days. Recovery is individual, but the intensity of physical and mental activity should gradually increase over time and should not exacerbate or worsen the symptoms.

Persistent symptoms

Formerly known as post-concussion syndrome, persistent post-concussion symptoms occur in around 1-10% those who have suffered a concussion. The exact prevalence is unknown due to methodological differences between studies and how persistent post-concussion symptoms are defined within these studies. As with concussion, persistent post-concussion symptoms vary among individuals but may include headaches, balance problems, light or noise sensitivity, anxiety and depression. We still don’t know why some people’s symptoms persist for many months, sometimes even years. But we suspect psychology may play a role. While the evidence is limited, early psychological intervention for those with ongoing symptoms, which involves educating the person on why they are feeling this way, has been shown to be effective at reducing the anxiety and depression that accompany persistent post-concussion symptoms. Despite psychological support, some express continued physical symptoms, such as headaches, balance problems, and light/noise sensitivity; reflecting possible changes or abnormalities in the brain. Fatigue, both mental and physical, is common in people with persistent post-concussion symptoms, but is often overlooked, despite it significantly impacting on quality of life.

What can measures of fatigue tell us?

Our new research suggests people with persistent post-concussion symptoms may have ongoing problems with fatigue and cognitive function because of changes to the way information is transmitted to and from their brain. We used transcranial magnetic stimulation, a non-invasive brain stimulation technique, to measure participants’ brain function and neural processing. When compared to both age-matched controls, as well as a group of people who have recovered from a previous concussion, we found people with persistent post-concussion symptoms were slower to complete the set activities – and their outcomes were more varied. We have previously compared brain responses via this method in retired Australian Rules and Rugby league players and found abnormal responses compared to other people of the same age with no history of head trauma. The next stage of our research is to better understand who is vulnerable to persistent post-concussion symptoms and how the condition can be treated. We understand how to diagnose and treat concussion in the short term, but we’re yet to uncover how to best assist people with persistent post-concussion symptoms to return to leading productive lives.   Alan Pearce, Associate Professor, School of Allied Health, La Trobe University This article is republished from The Conversation under a Creative Commons license. Read the original article.
By Prof Alan Pearce
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Dr Linda Calabresi
  • Clinical Articles

All benzos risky in pregnancy

Benzos increase the risk of having a miscarriage in early pregnancy, regardless of whether you’re taking a short-acting one for insomnia or a longer-acting one for anxiety, Canadian researchers say. According to their large case-controlled study involving almost 450,000 pregnancies, benzodiazepine exposure in early pregnancy was associated with an 85% higher risk of spontaneous abortion compared to pregnancies where that class of drugs were not taken. And this increased risk remained the same, after a whole range of possible confounders had been adjusted for, including maternal mood and anxiety disorders. But this isn’t the new bit. Previous research, including both a UK population-based study and an Israeli prospective study had confirmed the link between benzos and spontaneous abortion. In Australia, benzodiazepines have been given a Category C rating in terms of safety in pregnancy. (Drugs owing to their pharmacological effects have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations.) “Benzodiazepines cross the placental barrier and accumulate in the fetal circulation at levels that are one to three times higher than the maternal serum levels”, the researchers explained. What hasn’t been known, to date, is whether this is a class effect or are some benzos worse than others. Well – according to this study published in JAMA Psychiatry – ‘the risk was similar among pregnancies exposed to short-acting …and long-acting benzodiazepines during early pregnancy.’ So it didn’t matter if you were prescribed long-acting clonazepam or short-acting lorazepam (interestingly the two most frequently prescribed benzos), the risk was more or less the same. “All benzodiazepine agents were independently associated with an increased risk of [spontaneous abortion],” the study authors said. In addition the study found the risk increased as the daily dose of benzodiazepines increased, suggesting a dose-response effect. So basically the more doses of benzos a pregnant woman takes, either in terms of strength or duration, the greater the risk she will miscarry. Overall, the researchers concluded that pregnant women should avoid taking benzodiazepines, and if they have to take them only take the lowest dose possible for shortest duration possible. “Alternative nonpharmacologic treatments exist and are recommended, but if benzodiazepines are needed, they should be prescribed for short durations,” they concluded.  

Reference

Sheehy O, Zhao JP, Bérard A. Association Between Incident Exposure to Benzodiazepines in Early Pregnancy and Risk of Spontaneous Abortion. JAMA Psychiatry. 2019 May 15. DOI: 10.1001/jamapsychiatry.2019.0963 [Epub ahead of print]  
By Dr Linda Calabresi
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Dr Patty Thille
  • Clinical Articles

How anti-fat bias in health care endangers lives

When Ellen Maud Bennett died a year ago, her obituary published in the local newspaper gained national media attention in Canada, though she wasn’t a celebrity. Bennett’s obituary revealed she died from cancer days after finally being diagnosed — after years of seeking help. Her diagnosis came so late, beyond the point where treatments were possible, because the 64-year-old woman was repeatedly told her health problems were caused by her weight — or more specifically, by the amount of fat on her body. She died because of bad assumptions that caused poor quality care. And she used her own obituary to share her dying wish:
“Ellen’s dying wish was that women of size make her death matter by advocating strongly for their health and not accepting that fat is the only relevant health issue.”
How to know if this might be happening to you? When do you need to advocate for yourself? I studied the phenomenon of anti-fat stigma in Canadian primary care clinics for my PhD. Knowing how it happens might help.

Fatness as a sign of inferiority

Bodily fatness is a stigmatized body characteristic in Canada and other wealthy countries. Within any given culture, some characteristics or histories are assumed to reflect a character flaw. The characteristic is treated as a sign of inferiority. The result is loss of social status and widespread societal discrimination. With bodily fatness, the assumed character flaws are laziness, ignorance or weak willpower. In a comprehensive review published 10 years ago, there was strong evidence of fatness-related discrimination in employment, while other sectors were less researched. Studies carried out since that time confirm the pattern — including within health care.

‘Just eat more salads’

Poor quality clinical care due to anti-fat stigma occurs when doctors or nurses assume the stereotype holds true. One common way this happens: a clinician simply tells you to “lose weight,” as Bennett heard many times when seeking help. That’s like telling patients to “lose blood sugar.” Telling people to produce an outcome is not good quality clinical care. This is especially awful when weight is not related to the topic at hand — an ear infection, for example. Sometimes, clinicians do this as “opportunistic counselling.” It’s done assuming the benefits outweigh harms — except we know that doing this for weight reduces trust in health-care providers. And reduced trust can lead to avoidance, for obvious reasons — needs aren’t met. Unfortunately, some clinicians give very simplistic weight loss advice, such as “eat more salads,” without any assessment of what the patient already knows, does, has tried or can afford and fit into their lives. Simplistic advice is patronizing at best; it assumes patients are ignorant, as per the stereotype. This approach vastly underestimates the knowledge of a patient, gained in part through repeated past attempts to change body composition. One Canadian study found that half of those classified as overweight, and 71 per cent of those categorized as obese, had attempted to reduce their body weight in the last year. Simplistic messages — “lose weight” or “exercise more” — assume thinness is easy and simply involves some lifestyle tweaks. When such advice is given without assessment of health concerns — for instance, headaches — anti-fat biases can endanger lives.

Bias trumps science, sometimes

Clinicians should, at minimum, recommend actions that have a chance at producing an outcome. Lifestyle changes only produce modest effects for most, yet many clinicians assume much bigger impacts. Obesity Canada, an organization that uses evidence-based action to better prevent and manage obesity, reminds health-care providers that the typical body weight reduction from sustained lifestyle changes is five per cent of body weight. Dramatic life changes, such as those of participants on the TV show The Biggest Loser, can slow the body’s resting metabolic rate, triggering weight regain. Science also tells us that factors beyond lifestyle are influencing population shifts around body weight and fatness. But these scientific findings are still not routinely integrated into health-care professionals’ understandings of weight. As a result, many still emphasize poor willpower as the core problem. You shouldn’t have to advocate for yourself to get adequate health care. You should be able to trust your health-care professionals.

How to advocate for yourself

There are many people working to ensure access to good quality health care. But tackling discrimination is complex. You can help. When clinicians make one of these common mistakes or in some other way block you being diagnosed or treated, you are on good grounds to challenge them. Say something like: “What would you do if someone with a thin body had this problem?” Then encourage them to treat you in the same way. Send them this or other articles. Write your story and give it to them. Find a Health-At-Every-Size® practitioner, and check for local resources (such as the Good Fat Care website in Winnipeg). After receiving poor quality care, register a complaint with the provider’s professional licensing body. They may not investigate your individual complaint but do track trends. Patient advocates are also available in some hospitals to help you get the care you need. News stories come and go. But the issues Ellen Maud Bennett raised in her obituary should not disappear from our consciousness so quickly. You deserve good care, just as she did. This article is written in memory of Ellen Maud Bennett, with the permission of her sister.The Conversation Patty Thille, Assistant Professor in Physical Therapy, University of Manitoba This article is republished from The Conversation under a Creative Commons license. Read the original article.
By Dr Patty Thille
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Dr Linda Calabresi
  • Clinical Articles

Surprise benefit of glucosamine

Glucosamine’s effectiveness in treating arthritis remains controversial, however a study suggesting that the supplement, when taken regularly, will help prevent heart attacks certainly adds to its appeal. According to findings from a large prospective study just published in The BMJ, habitual glucosamine use is associated with a 15% lower risk of cardiovascular events. Breaking that down a bit further, it appears regular glucosamine lowered the risk of dying from a cardiovascular event by 22%, lowered the risk of coronary heart disease by 18% and lowered the risk of stroke by 9%. All statistically significant results. The research involved over 440,000 people from the UK biobank who didn’t have cardiovascular disease at the outset. Courtesy of an initial questionnaire, researchers knew who was taking glucosamine and how often. Interestingly about 20% of the cohort, reported they took the non-vitamin, non-mineral supplement daily – a figure the researchers said was representative in other adult populations around the world – including Australia. The cohort was then followed for a median of seven years. Over this time there were over 10,000 CVD events including heart attacks and strokes, with over 3,000 of these resulting in death. Even though the study was basically observational, the size of the sample strengthens its value. As does the fact that the researchers obtained a wealth of information about the patient’s diet, medical history and lifestyle at the initial questionnaire, which was all utilised in the final analysis. Consequently the 15% lower risk of a cardiovascular event associated with taking glucosamine can’t be easily written off as caused by another confounder. The researchers were able to conclude the association was “independent of traditional risk factors, including sex, age, income, body mass index, physical activity, healthy diet, alcohol intake, smoking status, diabetes, hypertension, high cholesterol, arthritis, drug use, and other supplement use.” So how does it work? How does glucosamine positively affect the cardiovascular system? According to the study authors, there are a number of plausible mechanisms that could explain the link. One relates to the anti-inflammatory properties of glucosamine. There already exists evidence that regular glucosamine reduces CRP levels, a marker of systemic inflammation. Another theory relates to how glucosamine affects metabolism. “[A] previous study found that glucosamine could mimic a low carbohydrate diet by decreasing glycolysis and increasing amino acid catabolism in mice; therefore, glucosamine has been treated as an energy restriction mimetic agent,” they said. But while the study findings appear very exciting, the study authors themselves suggest caution, claiming their study had some limitations. Among these limitations was the fact that details about the dose, duration of use, type of glucosamine supplement was not recorded. Obviously further research is needed to test this association. Nonetheless, the trial is destined to fuel on-going interest in the supplement, albeit for a totally different condition from the one we’re used to.  

References:

Ma H, Li X, Sun D, Zhou T, Ley SH, Gustat J, et al. Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank. BMJ. 2019 May 14; 365: l1628. DOI: 10.1136/bmj.l1628
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Pancreatic cancer support

It’s still probably one of medicine’s most devastating diagnoses – pancreatic cancer. Despite all the scientific advances that have been made in treating so many malignancies, the prognosis for pancreatic cancer is most often pretty bleak. Consequently, patients presented with this diagnosis are most likely to be in need of significant support. PanSupport (pansupport.org.au) is a newly-developed site, produced by the University of Melbourne that is likely to prove incredibly valuable to patients battling this condition, and their families. This resource not only provides valuable information about pancreatic cancer and its treatment, but it also gives practical advice with regard aspects of management such as diet and exercise. Importantly it also directs patients to any potential clinical trials for which they may be eligible. In keeping with the very practical and realistic approach of the entire site, Pansupport also includes information about palliative care and Advanced Care directives, allowing patients to access what they need to know in their own time frame. The PanSupport website has been developed in collaboration with the Pancare Foundation, RMIT University and the Peter MacCallum Cancer Centre. It has been funded with a Cancer Grant Initiative funded by the Australian Government. >> Find out more about PanSuport here 

By Dr Linda Calabresi
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Dr Edmond Chan
  • Clinical Articles

Peanut Allergies: Research Shows ‘Oral Immunotherapy’ is Safe for Preschoolers

  “We don’t have to live in fear anymore.” That’s the common refrain from hundreds of parents of preschoolers with peanut allergy that my colleagues and I have successfully treated with peanut “oral immunotherapy” over the past two years. Oral immunotherapy (OIT) is a treatment in which a patient consumes small amounts of an allergenic food, such as peanut, with the dose gradually increased to a target maximum (or maintenance) amount. The goal for most parents is to achieve desensitization — so their child can ingest more of the food without triggering a dangerous reaction, protecting them against accidental exposure. A recent study published in The Lancet has suggested that this treatment may make things worse for children with peanut allergies. The researchers behind the meta-analysis argue that children with peanut allergies should avoid peanuts. This study has limitations however. It did not include a single child under the age of five years old. And it runs the risk of confusing parents. My colleagues and I have seen firsthand that oral immunotherapy is not only safe, but is well tolerated in a large group of preschool children. We published data demonstrating this recently in the Journal of Allergy and Clinical Immunology: In Practice.  

Safe for preschoolers

For any parent of a child with severe allergy, the idea of giving them even a small amount of the allergenic food might give them pause. I don’t blame them — giving a child a known allergen is a daunting thought. Some allergists share this fear and do not offer OIT to patients in their clinics due to safety concerns. To assess the safety of oral immunotherapy, we followed 270 children across Canada between the ages of nine months and five years who were diagnosed with peanut allergy by an allergist. The children were fed a peanut dose, in a hospital or clinic, that gradually increased at every visit. Parents also gave children the same daily dose at home, between clinic visits, until they reached the maintenance dose. We found that 243 children (90 per cent) reached the maintenance stage successfully. Only 0.4 per cent of children experienced a severe allergic reaction. Out of over 40,000 peanut doses, only 12 went on to receive epinephrine (0.03 per cent). Our research provides the first real-world data that OIT is safe for preschool-aged children with peanut allergy when offered as routine treatment in a hospital or clinic, rather than within a clinical trial.  

The Lancet study was of older children

So why does the meta-analysis published in The Lancet show that peanut OIT increases allergic reactions, compared with avoidance or placebo? The researchers behind this study argue that avoidance of peanut is best for children with peanut allergy. They describe that in older children, the risk of anaphylaxis is 22.2 per cent and the risk of serious adverse events is 11.9 per cent. It is important for parents to note that The Lancet study only assessed children aged five and older participating in clinical trials (average age nine years old), and the researchers don’t even mention this as a limitation of their analysis. Our study, on the other hand, assessed preschool children (average age just under two years old) in the real world outside of research. While I agree that there are certainly more safety concerns in older children, and more research is needed to see which of them would most benefit, our results demonstrate with real-world data that, in preschoolers, OIT is a game-changer.  

For many patients, benefits outweigh risks

It isn’t rocket science that avoiding what one is allergic to will be safer than eating it. An analogy is knee replacement surgery. Of course, not having knee replacement surgery would be “safer” than having the surgery. But not having knee replacement surgery doesn’t provide any potential of benefits and also provides little hope for families. Likewise, telling parents of children with peanut allergy that avoidance is the only option outside research fails to take into account the negative long-term consequences of avoidance — such as poor quality of life, social isolation and anxiety. Allergists and the medical community as a whole must stop confusing parents with endless mixed messages about OIT both within and outside of research. The fact is, many allergists are already offering OIT outside of research. In our current era of basing medical treatment decisions on a comparison of risks versus benefits, there is simply no one-size-fits-all approach. Rather than concluding that all children with peanut allergy should be managed with avoidance, we should be concluding that there are some patients, such as preschoolers, for whom the benefits of offering this treatment outweigh the risks. OIT has proven to be effective in many studies, and we will similarly follow the progress of our patients long term to track effectiveness. The bottom line is this: OIT is safe for preschool children and should be considered for families of those very young children with peanut allergy who ask for it.The Conversation  

- Edmond Chan, Pediatric Allergist; Head & Clinical Associate Professor, Division of Allergy & Immunology, Department of Pediatrics, Faculty of Medicine; Investigator, BC Children's Hospital Research Institute, University of British Columbia

This article is republished from The Conversation under a Creative Commons license. Read the original article.
By Dr Edmond Chan
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Dr Linda Calabresi
  • Clinical Articles

Dysplastic naevi: the controversy continues

The entity ‘mildly dysplastic naevus’ has been removed from the World Health Organisation’s classification of dysplastic naevi. Dysplastic naevi are now to be graded as ‘low grade dysplastic naevus’ (previous moderately dysplastic naevus) or ‘high grade dysplastic naevus’ (previous severely dysplastic naevus).
  • Current data suggest no further treatment is necessary for lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia (previous mildly dysplastic and moderately dysplastic naevi) with clear histologic margins and no pigment evident clinically, unless there was a high level of prebiopsy clinical concern.
  • Re-excision with a 2-5mm clinical clearance is recommended for high grade dysplastic naevi (previous severely dysplastic naevi) with involved histologic margins.
  • There is growing evidence that observation may be reasonable for low grade dysplastic naevi (previous moderately dysplastic naevus) if they were excised with clinically clear margins/ no residual clinical pigment is observed, despite histologically involved margins. More data may be required before this is accepted into clinical practice.
  • There does not appear to be a clear consensus regarding whether high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm.
    •  

    Dysplastic naevus: the controversy since the 1970s

    The entity of dysplastic naevus has been shrouded in controversy since first described in the 1970s.1 This appears to be due to:
    1. Interobserver differences between histopathologists in applying the previous three tier grading system for dysplasia
    2. Perceived risk of progression to melanoma, and
    3. The possibility of benign entities simulating melanoma, all of which contribute to uncertainty and variability in management.2,3
    Dysplastic naevi are benign neoplasms of melanocytes.3 Dysplasia in melanocytes may occur de novo or in association with either congenital dermal naevi or common dermal naevi. It is probable that dysplasia arising in pre-existing naevi results from successive acquisition of genetic abnormalities.3 Both common naevi and dysplastic naevi demonstrate BRAF or NRAS mutations.3 It was at one time proposed that there is a step-wise model of tumour progression from dysplastic naevi through mild, to moderate, then severe dysplasia, and finally melanoma.4 However, there is no evidence that dysplastic naevi are, in fact, common precursors of melanoma.4 In actuality, the most common naevus remnant found in association with melanoma is the common acquired naevus.4 Given the large number of dysplastic naevi, compared with the comparatively small number of melanomas arising in association with dysplastic naevi, it seems that the rate of progression from dysplastic naevus to melanoma is extremely low.4 Dysplastic naevi seen associated with melanomas have an increased incidence of TERT promoter mutations, a common early genetic event in the evolution of melanoma in situ.3 This suggests that some dysplastic naevi are an intermediate entity between benign naevus and melanoma.3 There is a lack of data examining the frequency of similar genetic alterations in non-melanoma associated dysplastic naevi; thus, although the risk of progression is very low, it is suggested that naevi with high grade dysplasia or added genetic events (e.g. TERT promoter mutation) are considered for complete excision.3 It has been suggested that dysplastic naevi represent a marker of increased risk for an individual developing melanoma.5 It is difficult to establish the risk of melanoma at a separate site in patients with dysplastic naevi, as the reported incidence of dysplastic naevi in fair-skinned individuals varies widely (between 2% and 50%).4 One study has demonstrated that only the diameter of the dysplastic naevus had a significant association with a personal history of melanoma,6 whilst another study has shown that individuals with many naevi, whether common or dysplastic, have an increased risk of developing melanoma.7 Thus it would seem that two factors are associated with an individual’s risk of developing melanoma: a large number of common or dysplastic naevi (>100) and the larger size of the naevi (>4.4mm).6 It is generally agreed that there is low interobserver agreement between pathologists when grading dysplastic naevi, particularly in those lesions exhibiting moderate atypia to early in situ melanoma.8,9 This leads to uncertainty with regard to management of these lesions, especially if there is margin involvement. In 2017, Wall et al.2 conducted a survey investigating the management of dysplastic naevi by Australian dermatologists. This survey demonstrated that, similarly to comparable studies reported within the USA and Canada, most dermatologists would re-excise a moderately or severely dysplastic naevus with involved margins.2 There is, however, variability in Australian dermatologists’ approaches to severely dysplastic naevi (clinically concerning for melanoma) which are completely excised on biopsy, with 44% re-excising with a 5mm margin, and the remainder considering no further treatment necessary.2 In addition, whilst between 5-12% of US and Canadian dermatologists re-excise mildly dysplastic naevi involving margins, that rate in Australian dermatologists is 49%.2 A consensus statement released by Kim et al.10 in 2015 identified a critical gap in knowledge with regard to management of dysplastic naevi with involved margins. This consensus statement recommended that mildly to moderately dysplastic naevi with clear histologic margins need no re-excision. If a biopsy report reveals severe dysplasia with positive margins, re-excision to achieve a 2-5mm clinical margin is recommended. The statement suggested that mildly dysplastic naevi with positive histologic margins after biopsy (and no residual pigment) may be observed, and while observation may be a reasonable option for moderately dysplastic naevi with positive histologic margins (and no clinical pigment), more data are required to make a definitive recommendation.10 A further multi-centre retrospective cohort study in 2018 by Kim et al.11 suggests that close observation is a reasonable management approach for moderately dysplastic naevi with positive histologic margins. No specific recommendations are made regarding a severely dysplastic naevus with clear margins on biopsy.  

    WHO redefines melanocytic naevi

    The World Health Organisation (WHO) released their new Classification of Skin Tumours in 2018.3 They define dysplastic naevus as ‘a subset of melanocytic naevi that are clinically atypical and characterized histologically by architectural disorder and cytological atypia, always involving their junctional component.10 Diagnostic criteria for dysplastic naevi traditionally include a division of cytoarchitectural atypia into mild, moderate and severe categories.3 Pathologists often further subdivide these categories into ‘mild to moderate’ and ‘moderate to severe’ to reflect the histological field effect often perceived in these lesions. Lentiginous junctional or compound naevi (previously labelled mildly dysplastic naevi) are not associated with increased melanoma risk/progression to melanoma, and are also common within the population.3 The WHO consensus meeting working group recommends against the continued use of the term ‘mildly dysplastic naevus’ and instead recommends the use of low grade and high grade dysplasia. So, where are we now with these new recommendations regarding the grading of dysplastic naevi, and what are the management implications? It seems that the new WHO recommendations support the view that biopsies of the previously known mildly dysplastic naevi need no further treatment, having removed the entity from their classification. It would appear that there is agreement that dysplastic naevi with high grade dysplasia (previous severely dysplastic naevi) with involved margins requires re-excision to achieve a 2-5mm clinical margin of clearance. However, there appears to be no recommendations or clear consensus regarding whether these high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm. With regard to dysplastic naevi with low grade dysplasia (previous moderately dysplastic naevi), there is a slowly growing body of evidence to suggest that it may be reasonable for these cases to be observed if they were excised with clinically clear margins/no residual clinical pigment is observed, despite histologically involved margins. Given the current variation in clinical management of these lesions, as well as the continued lack of interobserver agreement between histopathologists when diagnosing these lesions, more data may be required before this recommendation is accepted. In conclusion, as the consensus statement by Kim et al.10 recommends, the decision to re-excise dysplastic naevi should be based on both the clinical and histologic findings. If the prebiopsy level of clinical concern is high, re-excision should be considered if the biopsy reveals positive margins, even if the level of histopathological dysplasia is low. In addition, there may be clinical scenarios warranting re-excision of a mildly, mildly-moderately/moderately dysplastic lesion (now known as lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia respectively), including patient preference.10  

    References:

    1. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era. J Am Acad Dermatol. 2012;67 (1): 1. E1-18. DOI: 10.1016/j.jaad.2012.03.013
    2. Wall N, De’Ambrosis B, Muir J. The management of dysplastic naevi: a survey of Australian dermatologists. Australasian Journal of Dermatology. 2017;58:304-307. DOI: 10.1111/ajd.12720
    3. Elder DE, Massi D, Scolyer RA, Willemze R, editors (2018). WHO classification of skin tumours. 4th Ed. Lyon: IARC.
    4. Busam KJ, Gerami P, Scolyer RA (2019). Pathology of Melanocytic Tumors. 1st Ed. Philadelphia: Elsevier.
    5. Elder DE. Dysplastic naevi: an update. Pathology. 2010;56(1):112-120.
    6. Xiong M, Rabkin M, Piepkorn M, Barnhill R, Argenyi Z, et al. Diameter of dysplastic naevi is a more robust bio marker of increased melanoma risk than degree of histologic dysplasia: a case-controlled study. J Am Acad Dermatol. 2014;71(6):12578.e4. DOI: https://doi.org/10.1016/j.jaad.2014.07.030
    7. Holly EA, Kelly JW, et al. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol. 1987;17:459-468. DOI: https://doi.org/10.1016/S0190-9622(87)70230-8
    8. Hiscox B, Hardin MR, Orengo IF, Rosen T, Mir M, Diwan AH: Recurrence of moderately dysplastic nevi with positive histological margins. J Am Acad Dermatol . 2017;76:527530.  DOI: 10.1016/j.jaad.2016.09.009
    9. Stefanato C. The “Dysplastic Nevus” Conundrum: A look back, a peek forward. Dermatopathology. 2018;5:53-57. DOl: https://doi.org/10.1159/000487924 
    10. Kim C, Swetter S, Curiel-Lewandrowski C, Grichnik J, Grossman D, et al. Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi. JAMA Dermatol. 2015;151(2):212218. DOI: 10.1001/jamadermatol.2014.2694
    11. Kim C, Berry E, Marchetti M, Swetter S, Liam G, et al. Risk of subsequent cutaneous melanoma in moderately dysplastic nevi excisional biopsies but with positive histologic margins. JAMA Dermatology. 2018;154(12):1401-1408 DOI: 10.1001/jamadermatol.2018.3359
      - General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.  
    By Dr Linda Calabresi
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    Prof Clare Collins
    • Clinical Articles

    Have you gone vegan? Keep an eye on these 4 nutrients

    There are many reasons people go vegan, from wanting to be healthier, to reducing their environmental footprint, to concerns about animal welfare. No matter what the reason, many people find it difficult to meet the nutrient intake targets for specific vitamins and minerals while on a vegan diet. These include vitamin B12, iron, calcium, and iodine. Here’s how to make sure you’re getting enough of these vitamins and minerals while following a vegan diet.

    1. Vitamin B12

    Vitamin B12, or cobalamin, is essential for making red blood cells, DNA (your genetic code), fatty acids located in myelin (which insulate nerves), and some neurotransmitters needed for brain function. Vitamin B12 is stored in the liver, so a deficiency probably won’t happen in adults in the short term.
    Symptoms of B12 deficiency
    Symptoms of vitamin B12 deficiency include tiredness, lethargy, low exercise tolerance, light-headedness, rapid heart rate or palpitations, bruising and bleeding easily, weight loss, impotence, bowel or bladder changes, a sore tongue, and bleeding gums. Other symptoms related to the nervous system include a loss of sensation in the hands or feet, problems related to movement, brain changes ranging from memory loss to mood changes or dementia, visual disturbances, and impaired bowel and bladder control.
    Testing for B12 deficiency
    Your doctor may request a blood test to check your vitamin B12 status and determine whether indicators are in the healthy range.
    Vegan food sources of B12
    Vitamin B12 is abundant in animal foods including meat, milk and dairy products. For vegans, plant sources of vitamin B12 include some algae and plants exposed to bacterial action or contaminated by soil or insects. While traces of vitamin B12 analogues can be found in some mushrooms, nori or fermented soy beans, more reliable sources include vitamin B12-supplemented soy or nut “milks”, or meat substitutes. Check the nutrition information panel on the label for the the B12 content. Crystalline vitamin B12 added to these products can boost the B12’s absorption rate to a level similar to that from animal products.

    2. Calcium

    Calcium is needed to develop and maintain the skeleton bones, and is stored in the teeth and bones. It is also essential for heart, muscle and nerve function.
    Testing for calcium deficiency
    Low calcium intakes are associated with osteoporosis or “brittle bones” and a higher risk of bone fractures. A bone scan is used to measure bone density, with osteoporosis diagnosed when bone density is low. Both low calcium intakes and low vitamin D levels increase the risk of osteoporosis. Check your bone health using the Know Your Bones online quiz.
    Vegan food sources of calcium
    Although the richest sources of calcium are milk and milk-based foods, vegans can get calcium from tofu or bean curd, some fortified soy or nut beverages, nuts, seeds, legumes, and breakfast cereals. Calcium needs can be higher for vegans and vegetarians due to the relatively high oxalic acid content of foods such as spinach, rhubarb, beans, and the high phytic acid content of seeds, nuts, grains, some raw beans, and soy products. These specific acids can lower the calcium absorption from these foods by 10-50%. In a study of calcium intakes of 1,475 adults , vegans were below national recommendations and had lower calcium intakes compared with vegetarians, semi-vegetarians, pesco-vegetarians, and omnivores.

    3. Iodine

    Iodine is needed to make thyroxine, a thyroid hormone used in normal growth, regulation of metabolic rate, and development of the central nervous system. Iodine is concentrated in the thyroid gland.
    Symptoms of iodine deficiency
    Iodine deficiency can lead to the enlargement of the thyroid gland, a goitre, or hypothyroidism. Symptoms of hypothyroidism include lethargy, tiredness, muscular weakness, feeling cold, difficulty concentrating, poor memory, weight gain, depression, facial puffiness, hair loss, dry skin, constipation, and slower heartbeat. In women, iodine deficiency can increase risk of miscarriage and stillbirth, and congenital anomalies, including mental retardation and cretinism.
    Testing for iodine deficiency
    Your iodine status can be assessed by a range of tests, including thyroid hormones in your blood, the size of your thyroid gland, or the presence of a goitre. Talk to your doctor about these tests.
    Vegan food sources of iodine
    The iodine content of food depends on the iodine content of plants, which in turn depends on soil iodine content. When soil content is low, iodine may need to be supplemented. Major sources of iodine are seafood, dairy products, and eggs. For vegans, iodised salt, commercial bread made using iodised salt, fortified soy or nut milks (check the product label) and seaweed are important. Substances called goitrogens, which are found in brassica vegetables – including cabbage, broccoli and Brussels sprouts, sweet potato and maize – can interfere with the production of thyroid hormones.

    4. Iron

    Iron is needed to make haemoglobin in red blood cells, which carries oxygen around your body. Iron is also needed for the production of energy in your muscles, and for concentration and a healthy immune system.
    Symptoms and testing for iron deficiency and anaemia
    Not having enough iron leads to iron deficiency, and is associated with reduced work capacity, impaired brain function, lower immunity, and delayed development in infants. The first stage of iron deficiency is referred to as low iron stores and your doctor may refer you for a blood test to check your iron status.
    Vegan food sources of iron
    In Australia and New Zealand, the biggest contributors to iron intake are wholegrain cereals, meats, chicken, and fish. The amount of iron absorbed from food depends on a person’s iron status (with those who are iron-deficient absorbing more), as well as the iron content of the entire meal, and whether iron is haem (from animal foods) or non-haem iron from plant sources such as grains and vegetables. Although iron from plant sources is less able to enter the body, you can boost your absorption by adding lemon or lime juice (citric acid) or other vitamin C-rich vegetables and fruits, which convert non-haem iron to a form than is better absorbed. Take care with food components that inhibit absorption of both haem and non-haem iron, including calcium, zinc and phytates in legumes, rice and other grains, and polyphenols and vegetable proteins that can inhibit absorption of non-haem iron. Long-term vegans will also need to keep an eye on levels of vitamin D, omega-3 fat and protein. A good strategy is to check in with your GP periodically to review your health and well-being, and an accredited practising dietitian can check whether you’re getting all the nutrients you need.The Conversation This article is republished from The Conversation under a Creative Commons license. Read the original article.
    By Prof Clare Collins
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    Dr Linda Calabresi
    • Clinical Articles

    Reproductive carrier screening

    Have you seen this? This little print-out could save you a good 30 minutes in valuable consulting time. It’s the information from Sonic for couples who are planning a family about the potential value for testing their carrier status for conditions such as cystic fibrosis and fragile X. Even though the information is coming from an organisation with a vested interest in promoting the testing, there is not even a suggestion of bias. It is all straight down the line – here are the risks – this is what is available for testing should you choose to pursue it. There’s no denying it is worth considering. RANZCOG recommends that information about reproductive carrier screening be offered to every woman either prior to conception (preferred) or in early pregnancy. Having this site bookmarked and ready to print off ensures your advice when advising women pre-conception is in keeping with best practice. >> Click here for resource

    By Dr Linda Calabresi
    Simple blood test a mortality predictor

    Smartvax

    It’s only been around a few years, but this little bit of technology has already received world wide acclaim for its ability to improve the safety of vaccines in the real-world setting. In simple terms, Smartvax is a program practices install into their software system that sends an SMS directly to patients three days after they receive a vaccination. Patients are asked if they experienced an adverse reaction to the vaccine. A straightforward Yes (Y) or No (N) is all that is required. A No reply ends the conversation, but a Yes will trigger a brief questionnaire that examines the nature of the adverse reaction. If the reaction resulted in the need to seek medical attention this is then flagged in the GP’s software inbox as well as with the local health authority. In practical terms this means adverse reactions are tracked in real time and act as an early warning signal that something could be amiss with a vaccine. Smartvax was developed by Perth GP, Dr Alan Leeb and Ian Peters, following a spate of serious and unexpected adverse reactions among young children who received one brand of flu vaccine back in 2010. It was apparent that a better, more time-sensitive system of monitoring side effects to vaccines was needed to ensure the safety of patients. With the widespread use of mobile phones, the day three post vax text has proven a very effective means of tracking reactions, with a high level of acceptance by patients. In a study from one NSW general practice, the response rate to the SMS  text was 85% post-childhood vaccination, and even in the over 65 year age range the response rate was 74%. Smartvax has now been adopted by more than 280 practices around Australia. The technology can also be used as a reminder system to prompt patients when their next vaccine is due. This is such a clever idea and as general practice becomes more and more tech savvy one can envisage a day when Smartvax is a basic requirement for all clinics that provide vaccinations.   >> Access the resource here

    By Dr Linda Calabresi
    Clinical Articles iconClinical Articles
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    Gene-directed prescribing coming to general practice

    It’s been around for some time now. The idea of checking a person’s genes to guide appropriate prescribing is not new. It is pretty much standard practice when treating many if not most cancers. But pharmacogenomics in general practice? Looking at an individual’s genetic variants to work out the best treatment for their depression, high cholesterol or gout? Yes – it’s coming. As authors of a recently published review in the Australian Journal of General Practice say, all practising clinicians will have had the experience of patients responding differently to medications despite every indication the medication should be effective, based on all the evidence from randomised controlled trials. It is known that certain genes that regulate the absorption, distribution, metabolism and excretion (ADME) of medications are commonly responsible for this difference in response, as these genes can vary between individuals. Researchers have also identified another group of genes that can influence medication responses directly, which, while less common can have important implications for prescribing. “For example, carbamazepine should not be prescribed to patients with certain human leucocyte antigen (HLA) genotypes because of an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis,” the Australian review authors said. Overall, there have been at least 15 genes identified for which testing can be useful and clinically beneficial in guiding prescribing of 30 different medications. How important will this be in general practice? According to this review at least, very. Firstly the likelihood of having a genetic variation that will influence how a person responds to a common medication is incredibly high. “A recent study of 5400 Australians who underwent testing of just four ADME genes showed that 96% had at least one clinically actionable pharmacogenomic variant,” the review authors said. And then the likelihood that a person will be prescribed one of the drugs that we can now predict the response based on genetic testing is also incredibly high. On analysis of PBS data from 2017, the researchers determined that in that year approximately 1.7 million Australians had filled a prescription for at least one the drugs that has the highest level of evidence of clinically relevant gene-medication association. In their review the authors present a number of case studies which demonstrate the usefulness of genetic testing in clinical practice. These include a patient with anxiety and depression who fails to respond to standard treatment leading to a significant deterioration of her condition. Genetic testing of CYP enzymes found the patient had a genetic variation that meant they rapidly metabolised certain antidepressants, but could be prescribed an alternative medication that wasn’t as dependent on the affected enzyme. Another example involved an older Han Chinese man who needed to be prescribed allopurinol for gout. Because this particular ethnicity has a 20% chance of carrying a gene that puts them at risk of developing severe cutaneous adverse reaction to allopurinol, gene testing was done to help ensure this risk was minimised. Similarly, a genetic variation that gives a higher than normal risk of muscle toxicity when taking simvastatin or atorvastatin can be tested for prior to patients being prescribed these medications, and a safer alternative statin offered. Fundamentally this type of testing will lead to more effective, safer prescribing. The problem is of course, pharmacogenomic testing does not attract a Medicare rebate in Australia and the cost is prohibitive for most patients, even though, according to the review authors the costs are decreasing all the time. A panel of common CYP enzymes now costs between $150 and $200. But the authors suggest this situation will have to change. Even on the basis of economics alone, the government needs to consider allowing rebates for at least some pharmacogenomic tests. “A report in 2008 estimated that the widespread implementation of such testing in Australia could yield savings in excess of $1 billion annually by the avoidance of adverse medication reactions alone,” they said. And imagine how much time, money and angst could be saved if doctors could ensure the first antidepressant a patient is prescribed had a high likelihood of having an effect, rather than the current trial and error approach. However while we wait for better reimbursement for this testing, the authors suggest the doctors consider using the tests where appropriate in patients who are prepared to pay. “Responsible doctors can use the tests and evidence that are already available to improve prescribing decisions for their patients,” they conclude.

    Reference

    Polasek TM, Mina K, Suthers G. Pharmacogenomics in general practice: The time has come. AJGP. 2019 March; 48(3): 100-5. Available from: https://www1.racgp.org.au/ajgp/2019/march/pharmacogenomics-in-general-practice
    By Dr Linda Calabresi
    Clinical Articles iconClinical Articles
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    Lactose intolerance and genetic testing

    A genetic test is now available to assist in the diagnosis of lactose intolerance in both children and adults.

    Key points

    • Lactose intolerance affects approximately 75% of the population.
    • Genetic testing can confirm lactose tolerance (also referred to as lactase persistence).
    • The test differentiates between primary lactose intolerance, due to lactase deficiency, and secondary causes of lactose intolerance, due to other more serious conditions that affect the small bowel.
    • The test is not affected by intercurrent illness and can be performed non-invasively on patients of all ages.
    The test only needs to be performed once during a person’s lifetime.

    How does the test work?

    Testing is now available to detect the genetic variant (LCT-13910C>T) that accounts for close to 100% of lactase persistence in Europeans. Three other genetic variants that have a similar effect and are more common in non-European populations are also detected. These variants are thought to act as enhancers of the lactase gene that in turn stimulates lactase production. When one of these variants is found, a diagnosis of primary lactose intolerance can be excluded. Lactose intolerance can be secondary to other conditions that affect the small bowel, such as gastroenteritis, inflammatory bowel disease and coeliac disease. Genotyping can help to distinguish these causes of intolerance.

    What causes lactose intolerance?

    Lactose is the major carbohydrate in mammalian milk. Lactose intolerance is caused by deficiency of lactase, the enzyme required for digestion of lactose. Symptoms include abdominal pain, diarrhoea, nausea, flatulence and/or bloating, following the consumption of lactose-containing foods.

    Who is affected by lactose intolerance?

    After infancy, approximately 75% of the population lose the ability to digest lactose, due to a deficiency in lactase, referred to as primary lactose intolerance. The remainder of people maintain their tolerance for lactose-containing foods because of genetic variants that enable continued production of lactase, referred to as lactase persistence. The prevalence of primary lactose intolerance varies significantly with ethnic background. Lactose intolerance is uncommon in populations that consume large amounts of dairy, for example, northern Europeans (as low as 10%), but is frequent in other populations (as high as 100% in Asiatic countries). It is hypothesised that this is the result of selective genetic advantage; populations that have historically been dependent on dairy food sources for nutrition have survived by having genetic variants that allow tolerance for lactose.

    Other testing alternatives

    Currently, testing for lactose intolerance can also be performed by a hydrogen breath test with lactose load, or by measurement of intestinal lactase enzyme activity in a biopsy obtained during endoscopy. These tests may give a false-positive result when lactase levels have been affected by a recent viral illness or coeliac disease. These procedures are also not suitable for testing children younger than seven years old. Genotyping is not affected by intercurrent illness and can be performed non-invasively on patients of all ages.

    Genetic testing limitations

    Please note that genotyping will not identify very rare genetic variants associated with persisting lactase activity, and therefore the absence of a variant can only be used to support a diagnosis of lactose intolerance along with other clinical and laboratory findings.

    Arranging a test

    1. Complete a standard pathology request form to refer the patient for ‘lactase persistence’ or ‘lactose intolerance genetic testing’.
    2. Collect or send the patient to a pathology collection centre for a blood test or buccal swab. No special preparation or booking is necessary.
    3. The result is reported back to the doctor, usually within five business days of the laboratory receiving the patient’s sample.

    Cost

    Medicare does not cover the cost of this test and the patient will receive an invoice for $75.*

    References

    • Bayless T, Brown E, Paige DM. Lactase non-persistence and lactose intolerance. Curr Gastroenterol Rep. 2017 May; 19(5): 23. DOI: 10.1007/s11894-017-0558-9
    • Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clin Exp Gastroenterol. 2012; 5: 113-21. DOI: 10.2147/CEG.S32368
    • Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet. 2007 Jan; 39(1): 31-40. DOI: 10.1038/ng1946
    • Heyman MB, Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep; 118(3): 1279-86. DOI: 10.1542/peds.2006-1721
    *Correct at time of printing. Please to refer to the Sonic Genetics website, www.sonicgenetics.com.au, for current pricing. General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.
    By Dr Kym Mina
    Clinical Articles iconClinical Articles
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    One in 10 patients have ongoing concussion symptoms

    Concussion is a temporary disturbance in brain function following an impact to the head. It can also occur after a blow to the body, if the force is transmitted to the head. Most people associate concussion with sports but they can occur anywhere, even at work or school. There are many signs and symptoms of concussion, which may present differently between individuals. These include headaches, nausea, vomiting, slurred speech, dizziness, temporary loss of memory, and inability to focus. Loss of consciousness only occurs in around 10% of concussions. Most people with concussions recover relatively quickly. Around 90% will recover within several days to a couple of weeks. But sometimes symptoms continue beyond a couple of weeks. When symptoms persist beyond three months, the person may be diagnosed as having persistent post-concussion symptoms.

    Rest is not always best

    We don’t know exactly how common concussions are, because they’re under-reported. Some people don’t think they are a serious injury, so don’t seek treatment, while others mask their injury because they don’t want to be seen as weak. The World Health Organisation classifies concussion, which is a type of traumatic brain injury, as a critical public health issue. Complete physical and mental rest used to be recommended after a concussion. Since 2017, however, the concussion treatment guidelines have evolved to reflect the science. While rest in the immediate 24-48 hours after a concussion is still advised, patients are now encouraged to undertake low-intensity exercise (such as walking, light jogging, or stationary cycling) and light mental stimulation (such as work or study) over the following days. Recovery is individual, but the intensity of physical and mental activity should gradually increase over time and should not exacerbate or worsen the symptoms.

    Persistent symptoms

    Formerly known as post-concussion syndrome, persistent post-concussion symptoms occur in around 1-10% those who have suffered a concussion. The exact prevalence is unknown due to methodological differences between studies and how persistent post-concussion symptoms are defined within these studies. As with concussion, persistent post-concussion symptoms vary among individuals but may include headaches, balance problems, light or noise sensitivity, anxiety and depression. We still don’t know why some people’s symptoms persist for many months, sometimes even years. But we suspect psychology may play a role. While the evidence is limited, early psychological intervention for those with ongoing symptoms, which involves educating the person on why they are feeling this way, has been shown to be effective at reducing the anxiety and depression that accompany persistent post-concussion symptoms. Despite psychological support, some express continued physical symptoms, such as headaches, balance problems, and light/noise sensitivity; reflecting possible changes or abnormalities in the brain. Fatigue, both mental and physical, is common in people with persistent post-concussion symptoms, but is often overlooked, despite it significantly impacting on quality of life.

    What can measures of fatigue tell us?

    Our new research suggests people with persistent post-concussion symptoms may have ongoing problems with fatigue and cognitive function because of changes to the way information is transmitted to and from their brain. We used transcranial magnetic stimulation, a non-invasive brain stimulation technique, to measure participants’ brain function and neural processing. When compared to both age-matched controls, as well as a group of people who have recovered from a previous concussion, we found people with persistent post-concussion symptoms were slower to complete the set activities – and their outcomes were more varied. We have previously compared brain responses via this method in retired Australian Rules and Rugby league players and found abnormal responses compared to other people of the same age with no history of head trauma. The next stage of our research is to better understand who is vulnerable to persistent post-concussion symptoms and how the condition can be treated. We understand how to diagnose and treat concussion in the short term, but we’re yet to uncover how to best assist people with persistent post-concussion symptoms to return to leading productive lives.   Alan Pearce, Associate Professor, School of Allied Health, La Trobe University This article is republished from The Conversation under a Creative Commons license. Read the original article.
    By Prof Alan Pearce
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    All benzos risky in pregnancy

    Benzos increase the risk of having a miscarriage in early pregnancy, regardless of whether you’re taking a short-acting one for insomnia or a longer-acting one for anxiety, Canadian researchers say. According to their large case-controlled study involving almost 450,000 pregnancies, benzodiazepine exposure in early pregnancy was associated with an 85% higher risk of spontaneous abortion compared to pregnancies where that class of drugs were not taken. And this increased risk remained the same, after a whole range of possible confounders had been adjusted for, including maternal mood and anxiety disorders. But this isn’t the new bit. Previous research, including both a UK population-based study and an Israeli prospective study had confirmed the link between benzos and spontaneous abortion. In Australia, benzodiazepines have been given a Category C rating in terms of safety in pregnancy. (Drugs owing to their pharmacological effects have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations.) “Benzodiazepines cross the placental barrier and accumulate in the fetal circulation at levels that are one to three times higher than the maternal serum levels”, the researchers explained. What hasn’t been known, to date, is whether this is a class effect or are some benzos worse than others. Well – according to this study published in JAMA Psychiatry – ‘the risk was similar among pregnancies exposed to short-acting …and long-acting benzodiazepines during early pregnancy.’ So it didn’t matter if you were prescribed long-acting clonazepam or short-acting lorazepam (interestingly the two most frequently prescribed benzos), the risk was more or less the same. “All benzodiazepine agents were independently associated with an increased risk of [spontaneous abortion],” the study authors said. In addition the study found the risk increased as the daily dose of benzodiazepines increased, suggesting a dose-response effect. So basically the more doses of benzos a pregnant woman takes, either in terms of strength or duration, the greater the risk she will miscarry. Overall, the researchers concluded that pregnant women should avoid taking benzodiazepines, and if they have to take them only take the lowest dose possible for shortest duration possible. “Alternative nonpharmacologic treatments exist and are recommended, but if benzodiazepines are needed, they should be prescribed for short durations,” they concluded.  

    Reference

    Sheehy O, Zhao JP, Bérard A. Association Between Incident Exposure to Benzodiazepines in Early Pregnancy and Risk of Spontaneous Abortion. JAMA Psychiatry. 2019 May 15. DOI: 10.1001/jamapsychiatry.2019.0963 [Epub ahead of print]  
    By Dr Linda Calabresi
    Clinical Articles iconClinical Articles
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    How anti-fat bias in health care endangers lives

    When Ellen Maud Bennett died a year ago, her obituary published in the local newspaper gained national media attention in Canada, though she wasn’t a celebrity. Bennett’s obituary revealed she died from cancer days after finally being diagnosed — after years of seeking help. Her diagnosis came so late, beyond the point where treatments were possible, because the 64-year-old woman was repeatedly told her health problems were caused by her weight — or more specifically, by the amount of fat on her body. She died because of bad assumptions that caused poor quality care. And she used her own obituary to share her dying wish:
    “Ellen’s dying wish was that women of size make her death matter by advocating strongly for their health and not accepting that fat is the only relevant health issue.”
    How to know if this might be happening to you? When do you need to advocate for yourself? I studied the phenomenon of anti-fat stigma in Canadian primary care clinics for my PhD. Knowing how it happens might help.

    Fatness as a sign of inferiority

    Bodily fatness is a stigmatized body characteristic in Canada and other wealthy countries. Within any given culture, some characteristics or histories are assumed to reflect a character flaw. The characteristic is treated as a sign of inferiority. The result is loss of social status and widespread societal discrimination. With bodily fatness, the assumed character flaws are laziness, ignorance or weak willpower. In a comprehensive review published 10 years ago, there was strong evidence of fatness-related discrimination in employment, while other sectors were less researched. Studies carried out since that time confirm the pattern — including within health care.

    ‘Just eat more salads’

    Poor quality clinical care due to anti-fat stigma occurs when doctors or nurses assume the stereotype holds true. One common way this happens: a clinician simply tells you to “lose weight,” as Bennett heard many times when seeking help. That’s like telling patients to “lose blood sugar.” Telling people to produce an outcome is not good quality clinical care. This is especially awful when weight is not related to the topic at hand — an ear infection, for example. Sometimes, clinicians do this as “opportunistic counselling.” It’s done assuming the benefits outweigh harms — except we know that doing this for weight reduces trust in health-care providers. And reduced trust can lead to avoidance, for obvious reasons — needs aren’t met. Unfortunately, some clinicians give very simplistic weight loss advice, such as “eat more salads,” without any assessment of what the patient already knows, does, has tried or can afford and fit into their lives. Simplistic advice is patronizing at best; it assumes patients are ignorant, as per the stereotype. This approach vastly underestimates the knowledge of a patient, gained in part through repeated past attempts to change body composition. One Canadian study found that half of those classified as overweight, and 71 per cent of those categorized as obese, had attempted to reduce their body weight in the last year. Simplistic messages — “lose weight” or “exercise more” — assume thinness is easy and simply involves some lifestyle tweaks. When such advice is given without assessment of health concerns — for instance, headaches — anti-fat biases can endanger lives.

    Bias trumps science, sometimes

    Clinicians should, at minimum, recommend actions that have a chance at producing an outcome. Lifestyle changes only produce modest effects for most, yet many clinicians assume much bigger impacts. Obesity Canada, an organization that uses evidence-based action to better prevent and manage obesity, reminds health-care providers that the typical body weight reduction from sustained lifestyle changes is five per cent of body weight. Dramatic life changes, such as those of participants on the TV show The Biggest Loser, can slow the body’s resting metabolic rate, triggering weight regain. Science also tells us that factors beyond lifestyle are influencing population shifts around body weight and fatness. But these scientific findings are still not routinely integrated into health-care professionals’ understandings of weight. As a result, many still emphasize poor willpower as the core problem. You shouldn’t have to advocate for yourself to get adequate health care. You should be able to trust your health-care professionals.

    How to advocate for yourself

    There are many people working to ensure access to good quality health care. But tackling discrimination is complex. You can help. When clinicians make one of these common mistakes or in some other way block you being diagnosed or treated, you are on good grounds to challenge them. Say something like: “What would you do if someone with a thin body had this problem?” Then encourage them to treat you in the same way. Send them this or other articles. Write your story and give it to them. Find a Health-At-Every-Size® practitioner, and check for local resources (such as the Good Fat Care website in Winnipeg). After receiving poor quality care, register a complaint with the provider’s professional licensing body. They may not investigate your individual complaint but do track trends. Patient advocates are also available in some hospitals to help you get the care you need. News stories come and go. But the issues Ellen Maud Bennett raised in her obituary should not disappear from our consciousness so quickly. You deserve good care, just as she did. This article is written in memory of Ellen Maud Bennett, with the permission of her sister.The Conversation Patty Thille, Assistant Professor in Physical Therapy, University of Manitoba This article is republished from The Conversation under a Creative Commons license. Read the original article.
    By Dr Patty Thille
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    Surprise benefit of glucosamine

    Glucosamine’s effectiveness in treating arthritis remains controversial, however a study suggesting that the supplement, when taken regularly, will help prevent heart attacks certainly adds to its appeal. According to findings from a large prospective study just published in The BMJ, habitual glucosamine use is associated with a 15% lower risk of cardiovascular events. Breaking that down a bit further, it appears regular glucosamine lowered the risk of dying from a cardiovascular event by 22%, lowered the risk of coronary heart disease by 18% and lowered the risk of stroke by 9%. All statistically significant results. The research involved over 440,000 people from the UK biobank who didn’t have cardiovascular disease at the outset. Courtesy of an initial questionnaire, researchers knew who was taking glucosamine and how often. Interestingly about 20% of the cohort, reported they took the non-vitamin, non-mineral supplement daily – a figure the researchers said was representative in other adult populations around the world – including Australia. The cohort was then followed for a median of seven years. Over this time there were over 10,000 CVD events including heart attacks and strokes, with over 3,000 of these resulting in death. Even though the study was basically observational, the size of the sample strengthens its value. As does the fact that the researchers obtained a wealth of information about the patient’s diet, medical history and lifestyle at the initial questionnaire, which was all utilised in the final analysis. Consequently the 15% lower risk of a cardiovascular event associated with taking glucosamine can’t be easily written off as caused by another confounder. The researchers were able to conclude the association was “independent of traditional risk factors, including sex, age, income, body mass index, physical activity, healthy diet, alcohol intake, smoking status, diabetes, hypertension, high cholesterol, arthritis, drug use, and other supplement use.” So how does it work? How does glucosamine positively affect the cardiovascular system? According to the study authors, there are a number of plausible mechanisms that could explain the link. One relates to the anti-inflammatory properties of glucosamine. There already exists evidence that regular glucosamine reduces CRP levels, a marker of systemic inflammation. Another theory relates to how glucosamine affects metabolism. “[A] previous study found that glucosamine could mimic a low carbohydrate diet by decreasing glycolysis and increasing amino acid catabolism in mice; therefore, glucosamine has been treated as an energy restriction mimetic agent,” they said. But while the study findings appear very exciting, the study authors themselves suggest caution, claiming their study had some limitations. Among these limitations was the fact that details about the dose, duration of use, type of glucosamine supplement was not recorded. Obviously further research is needed to test this association. Nonetheless, the trial is destined to fuel on-going interest in the supplement, albeit for a totally different condition from the one we’re used to.  

    References:

    Ma H, Li X, Sun D, Zhou T, Ley SH, Gustat J, et al. Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank. BMJ. 2019 May 14; 365: l1628. DOI: 10.1136/bmj.l1628
    By Dr Linda Calabresi
    Clinical Articles iconClinical Articles
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    Pancreatic cancer support

    It’s still probably one of medicine’s most devastating diagnoses – pancreatic cancer. Despite all the scientific advances that have been made in treating so many malignancies, the prognosis for pancreatic cancer is most often pretty bleak. Consequently, patients presented with this diagnosis are most likely to be in need of significant support. PanSupport (pansupport.org.au) is a newly-developed site, produced by the University of Melbourne that is likely to prove incredibly valuable to patients battling this condition, and their families. This resource not only provides valuable information about pancreatic cancer and its treatment, but it also gives practical advice with regard aspects of management such as diet and exercise. Importantly it also directs patients to any potential clinical trials for which they may be eligible. In keeping with the very practical and realistic approach of the entire site, Pansupport also includes information about palliative care and Advanced Care directives, allowing patients to access what they need to know in their own time frame. The PanSupport website has been developed in collaboration with the Pancare Foundation, RMIT University and the Peter MacCallum Cancer Centre. It has been funded with a Cancer Grant Initiative funded by the Australian Government. >> Find out more about PanSuport here 

    By Dr Linda Calabresi
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    Peanut Allergies: Research Shows ‘Oral Immunotherapy’ is Safe for Preschoolers

      “We don’t have to live in fear anymore.” That’s the common refrain from hundreds of parents of preschoolers with peanut allergy that my colleagues and I have successfully treated with peanut “oral immunotherapy” over the past two years. Oral immunotherapy (OIT) is a treatment in which a patient consumes small amounts of an allergenic food, such as peanut, with the dose gradually increased to a target maximum (or maintenance) amount. The goal for most parents is to achieve desensitization — so their child can ingest more of the food without triggering a dangerous reaction, protecting them against accidental exposure. A recent study published in The Lancet has suggested that this treatment may make things worse for children with peanut allergies. The researchers behind the meta-analysis argue that children with peanut allergies should avoid peanuts. This study has limitations however. It did not include a single child under the age of five years old. And it runs the risk of confusing parents. My colleagues and I have seen firsthand that oral immunotherapy is not only safe, but is well tolerated in a large group of preschool children. We published data demonstrating this recently in the Journal of Allergy and Clinical Immunology: In Practice.  

    Safe for preschoolers

    For any parent of a child with severe allergy, the idea of giving them even a small amount of the allergenic food might give them pause. I don’t blame them — giving a child a known allergen is a daunting thought. Some allergists share this fear and do not offer OIT to patients in their clinics due to safety concerns. To assess the safety of oral immunotherapy, we followed 270 children across Canada between the ages of nine months and five years who were diagnosed with peanut allergy by an allergist. The children were fed a peanut dose, in a hospital or clinic, that gradually increased at every visit. Parents also gave children the same daily dose at home, between clinic visits, until they reached the maintenance dose. We found that 243 children (90 per cent) reached the maintenance stage successfully. Only 0.4 per cent of children experienced a severe allergic reaction. Out of over 40,000 peanut doses, only 12 went on to receive epinephrine (0.03 per cent). Our research provides the first real-world data that OIT is safe for preschool-aged children with peanut allergy when offered as routine treatment in a hospital or clinic, rather than within a clinical trial.  

    The Lancet study was of older children

    So why does the meta-analysis published in The Lancet show that peanut OIT increases allergic reactions, compared with avoidance or placebo? The researchers behind this study argue that avoidance of peanut is best for children with peanut allergy. They describe that in older children, the risk of anaphylaxis is 22.2 per cent and the risk of serious adverse events is 11.9 per cent. It is important for parents to note that The Lancet study only assessed children aged five and older participating in clinical trials (average age nine years old), and the researchers don’t even mention this as a limitation of their analysis. Our study, on the other hand, assessed preschool children (average age just under two years old) in the real world outside of research. While I agree that there are certainly more safety concerns in older children, and more research is needed to see which of them would most benefit, our results demonstrate with real-world data that, in preschoolers, OIT is a game-changer.  

    For many patients, benefits outweigh risks

    It isn’t rocket science that avoiding what one is allergic to will be safer than eating it. An analogy is knee replacement surgery. Of course, not having knee replacement surgery would be “safer” than having the surgery. But not having knee replacement surgery doesn’t provide any potential of benefits and also provides little hope for families. Likewise, telling parents of children with peanut allergy that avoidance is the only option outside research fails to take into account the negative long-term consequences of avoidance — such as poor quality of life, social isolation and anxiety. Allergists and the medical community as a whole must stop confusing parents with endless mixed messages about OIT both within and outside of research. The fact is, many allergists are already offering OIT outside of research. In our current era of basing medical treatment decisions on a comparison of risks versus benefits, there is simply no one-size-fits-all approach. Rather than concluding that all children with peanut allergy should be managed with avoidance, we should be concluding that there are some patients, such as preschoolers, for whom the benefits of offering this treatment outweigh the risks. OIT has proven to be effective in many studies, and we will similarly follow the progress of our patients long term to track effectiveness. The bottom line is this: OIT is safe for preschool children and should be considered for families of those very young children with peanut allergy who ask for it.The Conversation  

    - Edmond Chan, Pediatric Allergist; Head & Clinical Associate Professor, Division of Allergy & Immunology, Department of Pediatrics, Faculty of Medicine; Investigator, BC Children's Hospital Research Institute, University of British Columbia

    This article is republished from The Conversation under a Creative Commons license. Read the original article.
    By Dr Edmond Chan
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    Dysplastic naevi: the controversy continues

    The entity ‘mildly dysplastic naevus’ has been removed from the World Health Organisation’s classification of dysplastic naevi. Dysplastic naevi are now to be graded as ‘low grade dysplastic naevus’ (previous moderately dysplastic naevus) or ‘high grade dysplastic naevus’ (previous severely dysplastic naevus).
  • Current data suggest no further treatment is necessary for lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia (previous mildly dysplastic and moderately dysplastic naevi) with clear histologic margins and no pigment evident clinically, unless there was a high level of prebiopsy clinical concern.
  • Re-excision with a 2-5mm clinical clearance is recommended for high grade dysplastic naevi (previous severely dysplastic naevi) with involved histologic margins.
  • There is growing evidence that observation may be reasonable for low grade dysplastic naevi (previous moderately dysplastic naevus) if they were excised with clinically clear margins/ no residual clinical pigment is observed, despite histologically involved margins. More data may be required before this is accepted into clinical practice.
  • There does not appear to be a clear consensus regarding whether high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm.
    •  

    Dysplastic naevus: the controversy since the 1970s

    The entity of dysplastic naevus has been shrouded in controversy since first described in the 1970s.1 This appears to be due to:
    1. Interobserver differences between histopathologists in applying the previous three tier grading system for dysplasia
    2. Perceived risk of progression to melanoma, and
    3. The possibility of benign entities simulating melanoma, all of which contribute to uncertainty and variability in management.2,3
    Dysplastic naevi are benign neoplasms of melanocytes.3 Dysplasia in melanocytes may occur de novo or in association with either congenital dermal naevi or common dermal naevi. It is probable that dysplasia arising in pre-existing naevi results from successive acquisition of genetic abnormalities.3 Both common naevi and dysplastic naevi demonstrate BRAF or NRAS mutations.3 It was at one time proposed that there is a step-wise model of tumour progression from dysplastic naevi through mild, to moderate, then severe dysplasia, and finally melanoma.4 However, there is no evidence that dysplastic naevi are, in fact, common precursors of melanoma.4 In actuality, the most common naevus remnant found in association with melanoma is the common acquired naevus.4 Given the large number of dysplastic naevi, compared with the comparatively small number of melanomas arising in association with dysplastic naevi, it seems that the rate of progression from dysplastic naevus to melanoma is extremely low.4 Dysplastic naevi seen associated with melanomas have an increased incidence of TERT promoter mutations, a common early genetic event in the evolution of melanoma in situ.3 This suggests that some dysplastic naevi are an intermediate entity between benign naevus and melanoma.3 There is a lack of data examining the frequency of similar genetic alterations in non-melanoma associated dysplastic naevi; thus, although the risk of progression is very low, it is suggested that naevi with high grade dysplasia or added genetic events (e.g. TERT promoter mutation) are considered for complete excision.3 It has been suggested that dysplastic naevi represent a marker of increased risk for an individual developing melanoma.5 It is difficult to establish the risk of melanoma at a separate site in patients with dysplastic naevi, as the reported incidence of dysplastic naevi in fair-skinned individuals varies widely (between 2% and 50%).4 One study has demonstrated that only the diameter of the dysplastic naevus had a significant association with a personal history of melanoma,6 whilst another study has shown that individuals with many naevi, whether common or dysplastic, have an increased risk of developing melanoma.7 Thus it would seem that two factors are associated with an individual’s risk of developing melanoma: a large number of common or dysplastic naevi (>100) and the larger size of the naevi (>4.4mm).6 It is generally agreed that there is low interobserver agreement between pathologists when grading dysplastic naevi, particularly in those lesions exhibiting moderate atypia to early in situ melanoma.8,9 This leads to uncertainty with regard to management of these lesions, especially if there is margin involvement. In 2017, Wall et al.2 conducted a survey investigating the management of dysplastic naevi by Australian dermatologists. This survey demonstrated that, similarly to comparable studies reported within the USA and Canada, most dermatologists would re-excise a moderately or severely dysplastic naevus with involved margins.2 There is, however, variability in Australian dermatologists’ approaches to severely dysplastic naevi (clinically concerning for melanoma) which are completely excised on biopsy, with 44% re-excising with a 5mm margin, and the remainder considering no further treatment necessary.2 In addition, whilst between 5-12% of US and Canadian dermatologists re-excise mildly dysplastic naevi involving margins, that rate in Australian dermatologists is 49%.2 A consensus statement released by Kim et al.10 in 2015 identified a critical gap in knowledge with regard to management of dysplastic naevi with involved margins. This consensus statement recommended that mildly to moderately dysplastic naevi with clear histologic margins need no re-excision. If a biopsy report reveals severe dysplasia with positive margins, re-excision to achieve a 2-5mm clinical margin is recommended. The statement suggested that mildly dysplastic naevi with positive histologic margins after biopsy (and no residual pigment) may be observed, and while observation may be a reasonable option for moderately dysplastic naevi with positive histologic margins (and no clinical pigment), more data are required to make a definitive recommendation.10 A further multi-centre retrospective cohort study in 2018 by Kim et al.11 suggests that close observation is a reasonable management approach for moderately dysplastic naevi with positive histologic margins. No specific recommendations are made regarding a severely dysplastic naevus with clear margins on biopsy.  

    WHO redefines melanocytic naevi

    The World Health Organisation (WHO) released their new Classification of Skin Tumours in 2018.3 They define dysplastic naevus as ‘a subset of melanocytic naevi that are clinically atypical and characterized histologically by architectural disorder and cytological atypia, always involving their junctional component.10 Diagnostic criteria for dysplastic naevi traditionally include a division of cytoarchitectural atypia into mild, moderate and severe categories.3 Pathologists often further subdivide these categories into ‘mild to moderate’ and ‘moderate to severe’ to reflect the histological field effect often perceived in these lesions. Lentiginous junctional or compound naevi (previously labelled mildly dysplastic naevi) are not associated with increased melanoma risk/progression to melanoma, and are also common within the population.3 The WHO consensus meeting working group recommends against the continued use of the term ‘mildly dysplastic naevus’ and instead recommends the use of low grade and high grade dysplasia. So, where are we now with these new recommendations regarding the grading of dysplastic naevi, and what are the management implications? It seems that the new WHO recommendations support the view that biopsies of the previously known mildly dysplastic naevi need no further treatment, having removed the entity from their classification. It would appear that there is agreement that dysplastic naevi with high grade dysplasia (previous severely dysplastic naevi) with involved margins requires re-excision to achieve a 2-5mm clinical margin of clearance. However, there appears to be no recommendations or clear consensus regarding whether these high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm. With regard to dysplastic naevi with low grade dysplasia (previous moderately dysplastic naevi), there is a slowly growing body of evidence to suggest that it may be reasonable for these cases to be observed if they were excised with clinically clear margins/no residual clinical pigment is observed, despite histologically involved margins. Given the current variation in clinical management of these lesions, as well as the continued lack of interobserver agreement between histopathologists when diagnosing these lesions, more data may be required before this recommendation is accepted. In conclusion, as the consensus statement by Kim et al.10 recommends, the decision to re-excise dysplastic naevi should be based on both the clinical and histologic findings. If the prebiopsy level of clinical concern is high, re-excision should be considered if the biopsy reveals positive margins, even if the level of histopathological dysplasia is low. In addition, there may be clinical scenarios warranting re-excision of a mildly, mildly-moderately/moderately dysplastic lesion (now known as lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia respectively), including patient preference.10  

    References:

    1. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era. J Am Acad Dermatol. 2012;67 (1): 1. E1-18. DOI: 10.1016/j.jaad.2012.03.013
    2. Wall N, De’Ambrosis B, Muir J. The management of dysplastic naevi: a survey of Australian dermatologists. Australasian Journal of Dermatology. 2017;58:304-307. DOI: 10.1111/ajd.12720
    3. Elder DE, Massi D, Scolyer RA, Willemze R, editors (2018). WHO classification of skin tumours. 4th Ed. Lyon: IARC.
    4. Busam KJ, Gerami P, Scolyer RA (2019). Pathology of Melanocytic Tumors. 1st Ed. Philadelphia: Elsevier.
    5. Elder DE. Dysplastic naevi: an update. Pathology. 2010;56(1):112-120.
    6. Xiong M, Rabkin M, Piepkorn M, Barnhill R, Argenyi Z, et al. Diameter of dysplastic naevi is a more robust bio marker of increased melanoma risk than degree of histologic dysplasia: a case-controlled study. J Am Acad Dermatol. 2014;71(6):12578.e4. DOI: https://doi.org/10.1016/j.jaad.2014.07.030
    7. Holly EA, Kelly JW, et al. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol. 1987;17:459-468. DOI: https://doi.org/10.1016/S0190-9622(87)70230-8
    8. Hiscox B, Hardin MR, Orengo IF, Rosen T, Mir M, Diwan AH: Recurrence of moderately dysplastic nevi with positive histological margins. J Am Acad Dermatol . 2017;76:527530.  DOI: 10.1016/j.jaad.2016.09.009
    9. Stefanato C. The “Dysplastic Nevus” Conundrum: A look back, a peek forward. Dermatopathology. 2018;5:53-57. DOl: https://doi.org/10.1159/000487924 
    10. Kim C, Swetter S, Curiel-Lewandrowski C, Grichnik J, Grossman D, et al. Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi. JAMA Dermatol. 2015;151(2):212218. DOI: 10.1001/jamadermatol.2014.2694
    11. Kim C, Berry E, Marchetti M, Swetter S, Liam G, et al. Risk of subsequent cutaneous melanoma in moderately dysplastic nevi excisional biopsies but with positive histologic margins. JAMA Dermatology. 2018;154(12):1401-1408 DOI: 10.1001/jamadermatol.2018.3359
      - General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.  
    By Dr Linda Calabresi
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    Have you gone vegan? Keep an eye on these 4 nutrients

    There are many reasons people go vegan, from wanting to be healthier, to reducing their environmental footprint, to concerns about animal welfare. No matter what the reason, many people find it difficult to meet the nutrient intake targets for specific vitamins and minerals while on a vegan diet. These include vitamin B12, iron, calcium, and iodine. Here’s how to make sure you’re getting enough of these vitamins and minerals while following a vegan diet.

    1. Vitamin B12

    Vitamin B12, or cobalamin, is essential for making red blood cells, DNA (your genetic code), fatty acids located in myelin (which insulate nerves), and some neurotransmitters needed for brain function. Vitamin B12 is stored in the liver, so a deficiency probably won’t happen in adults in the short term.
    Symptoms of B12 deficiency
    Symptoms of vitamin B12 deficiency include tiredness, lethargy, low exercise tolerance, light-headedness, rapid heart rate or palpitations, bruising and bleeding easily, weight loss, impotence, bowel or bladder changes, a sore tongue, and bleeding gums. Other symptoms related to the nervous system include a loss of sensation in the hands or feet, problems related to movement, brain changes ranging from memory loss to mood changes or dementia, visual disturbances, and impaired bowel and bladder control.
    Testing for B12 deficiency
    Your doctor may request a blood test to check your vitamin B12 status and determine whether indicators are in the healthy range.
    Vegan food sources of B12
    Vitamin B12 is abundant in animal foods including meat, milk and dairy products. For vegans, plant sources of vitamin B12 include some algae and plants exposed to bacterial action or contaminated by soil or insects. While traces of vitamin B12 analogues can be found in some mushrooms, nori or fermented soy beans, more reliable sources include vitamin B12-supplemented soy or nut “milks”, or meat substitutes. Check the nutrition information panel on the label for the the B12 content. Crystalline vitamin B12 added to these products can boost the B12’s absorption rate to a level similar to that from animal products.

    2. Calcium

    Calcium is needed to develop and maintain the skeleton bones, and is stored in the teeth and bones. It is also essential for heart, muscle and nerve function.
    Testing for calcium deficiency
    Low calcium intakes are associated with osteoporosis or “brittle bones” and a higher risk of bone fractures. A bone scan is used to measure bone density, with osteoporosis diagnosed when bone density is low. Both low calcium intakes and low vitamin D levels increase the risk of osteoporosis. Check your bone health using the Know Your Bones online quiz.
    Vegan food sources of calcium
    Although the richest sources of calcium are milk and milk-based foods, vegans can get calcium from tofu or bean curd, some fortified soy or nut beverages, nuts, seeds, legumes, and breakfast cereals. Calcium needs can be higher for vegans and vegetarians due to the relatively high oxalic acid content of foods such as spinach, rhubarb, beans, and the high phytic acid content of seeds, nuts, grains, some raw beans, and soy products. These specific acids can lower the calcium absorption from these foods by 10-50%. In a study of calcium intakes of 1,475 adults , vegans were below national recommendations and had lower calcium intakes compared with vegetarians, semi-vegetarians, pesco-vegetarians, and omnivores.

    3. Iodine

    Iodine is needed to make thyroxine, a thyroid hormone used in normal growth, regulation of metabolic rate, and development of the central nervous system. Iodine is concentrated in the thyroid gland.
    Symptoms of iodine deficiency
    Iodine deficiency can lead to the enlargement of the thyroid gland, a goitre, or hypothyroidism. Symptoms of hypothyroidism include lethargy, tiredness, muscular weakness, feeling cold, difficulty concentrating, poor memory, weight gain, depression, facial puffiness, hair loss, dry skin, constipation, and slower heartbeat. In women, iodine deficiency can increase risk of miscarriage and stillbirth, and congenital anomalies, including mental retardation and cretinism.
    Testing for iodine deficiency
    Your iodine status can be assessed by a range of tests, including thyroid hormones in your blood, the size of your thyroid gland, or the presence of a goitre. Talk to your doctor about these tests.
    Vegan food sources of iodine
    The iodine content of food depends on the iodine content of plants, which in turn depends on soil iodine content. When soil content is low, iodine may need to be supplemented. Major sources of iodine are seafood, dairy products, and eggs. For vegans, iodised salt, commercial bread made using iodised salt, fortified soy or nut milks (check the product label) and seaweed are important. Substances called goitrogens, which are found in brassica vegetables – including cabbage, broccoli and Brussels sprouts, sweet potato and maize – can interfere with the production of thyroid hormones.

    4. Iron

    Iron is needed to make haemoglobin in red blood cells, which carries oxygen around your body. Iron is also needed for the production of energy in your muscles, and for concentration and a healthy immune system.
    Symptoms and testing for iron deficiency and anaemia
    Not having enough iron leads to iron deficiency, and is associated with reduced work capacity, impaired brain function, lower immunity, and delayed development in infants. The first stage of iron deficiency is referred to as low iron stores and your doctor may refer you for a blood test to check your iron status.
    Vegan food sources of iron
    In Australia and New Zealand, the biggest contributors to iron intake are wholegrain cereals, meats, chicken, and fish. The amount of iron absorbed from food depends on a person’s iron status (with those who are iron-deficient absorbing more), as well as the iron content of the entire meal, and whether iron is haem (from animal foods) or non-haem iron from plant sources such as grains and vegetables. Although iron from plant sources is less able to enter the body, you can boost your absorption by adding lemon or lime juice (citric acid) or other vitamin C-rich vegetables and fruits, which convert non-haem iron to a form than is better absorbed. Take care with food components that inhibit absorption of both haem and non-haem iron, including calcium, zinc and phytates in legumes, rice and other grains, and polyphenols and vegetable proteins that can inhibit absorption of non-haem iron. Long-term vegans will also need to keep an eye on levels of vitamin D, omega-3 fat and protein. A good strategy is to check in with your GP periodically to review your health and well-being, and an accredited practising dietitian can check whether you’re getting all the nutrients you need.The Conversation This article is republished from The Conversation under a Creative Commons license. Read the original article.
    By Prof Clare Collins
    Clinical Articles iconClinical Articles
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    Reproductive carrier screening

    Have you seen this? This little print-out could save you a good 30 minutes in valuable consulting time. It’s the information from Sonic for couples who are planning a family about the potential value for testing their carrier status for conditions such as cystic fibrosis and fragile X. Even though the information is coming from an organisation with a vested interest in promoting the testing, there is not even a suggestion of bias. It is all straight down the line – here are the risks – this is what is available for testing should you choose to pursue it. There’s no denying it is worth considering. RANZCOG recommends that information about reproductive carrier screening be offered to every woman either prior to conception (preferred) or in early pregnancy. Having this site bookmarked and ready to print off ensures your advice when advising women pre-conception is in keeping with best practice. >> Click here for resource

    By Dr Linda Calabresi
    Clinical Articles iconClinical Articles

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