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Articles

Read the latest articles relevant to your clinical practice, including exclusive insights from Healthed surveys and polls.

By reading selected clinical articles, you earn CPD in the Educational Activities (EA) category whenever you click the “Claim CPD” button and follow the prompts. 

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Dr Linda Calabresi
  • Clinical Articles

Are We Missing Chronic Pancreatitis? Does it Matter?

The answer to both these questions is yes according to Dr Darren Pavey, gastroenterologist and senior lecturer at the University of NSW. Speaking at the Healthed General Practice Education seminar in Sydney recently, Dr Pavey said there was good international research suggesting that many cases of chronic pancreatitis were going undiagnosed and the condition was far more prevalent than previously recognised. Overseas studies including cohorts of randomly selected adult patients suggest a prevalence of between 6-12%, with the condition being more likely among patients with recent onset type 2 diabetes, excess alcohol intake, smokers and those over 40 years of age, he said. And in response to the question of whether it is important to diagnose this condition, Dr Pavey said chronic pancreatitis not only caused immediate symptoms usually including pain, diarrhoea and weight loss but commonly had longer-term consequences such as pancreatic exocrine insufficiency (where there is less than 10% pancreatic function) and an increased risk of diabetes, malnutrition and even pancreatic cancer. Certainly, an incentive to diagnose and treat earlier rather than later. Part of the challenge in recognising the condition is that the classic triad of symptoms, namely abdominal pain, diarrhoea and weight loss are common to a variety of medical conditions including IBD and IBS. What’s more, abdominal pain, which many doctors would have thought had to be present with pancreatitis does not always occur in chronic pancreatitis especially when it is idiopathic which is the more common variety of chronic pancreatitis. In fact, pain is only present in about half the cases of idiopathic chronic pancreatitis. Idiopathic pancreatitis constitute 55% of all cases, the other 45% being alcohol-related. Abdominal pain tends to be a more consistent feature of alcoholic chronic pancreatitis. So if you have a patient in the right age group (about 40 to 60 years), who has chronic diarrhoea, weight loss and maybe abdominal pain and you suspect they might have chronic pancreatitis what do you do? The most common screening test for chronic pancreatitis is now a faecal elastase-1 stool test, requiring a single formed stool sample, said Dr Pavey. The test has a high specificity and sensitivity (both over 90%) and is readily available to Australian GPs, although it does not attract a Medicare rebate and costs approximately $60. The test is positive if the concentration of faecal elastase is less than 200mcg/g. In terms of imaging, CT is usually the option of first choice with signs of calcification and atrophy being pathognomonic of significant chronic pancreatitis. Aside from the need to stop drinking and smoking, treatment revolves around replacement of the pancreatic enzymes, which is available as a capsule taken orally (Creon). The deficiency of these enzymes is the chief cause of the diarrhoea, malabsorption, and weight loss so replacing them not only alleviates the symptoms but will also help prevent some of significant sequelae associated with this ongoing condition. Interestingly, a study of patients newly diagnosed with pancreatic cancer, showed that 66% had pancreatic exocrine insufficiency at diagnosis, and after two months this prevalence grew to 93% Dr Pavey advises starting patients with known chronic pancreatitis on 25,000 lipase units (Creon) with every meal and 10,000 units with every snack, and recommends patients eat six smaller meals during the day rather than three larger meals. This replacement therapy would then be titrated up to 40,000 units with a meal and 25,000 units for a snack. For those whose need was greater, replacement could even be increased to 80,000 units per meal. There was no need to put patients on a reduced fat diet when they were on pancreatic enzyme replacement therapy however they often had a highly acidic upper gastrointestinal environment and required acid suppression treatment. In conclusion, Dr Pavey advises clinicians to have a high index of suspicion for this poorly-recognised but important condition. “[Doctors] should be aware of the problem of underdiagnosing this condition and have a low threshold for checking faecal elastase and assessing pancreatic insufficiency,” he said.

By Dr Linda Calabresi
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Dr Alistair McGregor
  • Clinical Articles

Infection Risk in Asplenia and Hyposplenism

It is estimated that up to 25,000 Australians are affected by asplenia or hyposplenism.1  Many are unaware of the fact, and its potential consequences. The spleen plays an important role in immune function, in particular the prevention of infection due to some specific organisms (Table 1).

Infection Risk

Infection is a relatively common occurrence in those without a functioning spleen. Overwhelming post-splenectomy infection (OPSI), occurs in up to 5% of asplenic patients and has a mortality rate of over 50%. The risk is particularly high in children aged under five, and in the first three years post-splenectomy. However, the risk is lifelong.1

Organisms of Concern

Table 1:     Organisms of Concern
Agent Comment
Streptococcus pneumoniae Accounts for >50% of severe infections. Vaccine available and recommended
Neiserria meningitidis Vaccine available and recommended.
Haemophilus influenza type B Vaccine available and recommended.
Capnocytophagia species Oral flora in animals. Risk of acquisition after animal bites.
Bordetella holmesii Newly recognised pathogen.
Plasmodia species (Malaria) Babesia, Ehrlichia Potential risk for travellers. Seek pre-travel advice.
 

Causes of Asplenia and Hyposplenism

Asplenia maybe congenital but is more often acquired as a result of trauma or the surgical removal of the spleen due to haematological conditions, or after incidental splenic damage incurred during intra-abdominal surgery. Functional hyposplenism also confers an increased risk of infection and may occur as a result of a number of medical conditions (Table 2).   Table 2:    Medical conditions associated with hyposplenism
Coeliac disease
SLE
Sickle Cell disease
Rheumatoid arthritis
Malignant infiltration e.g. lymphoma
Splenic infarction or radiation
Graft versus host disease
 

Detection of Asplenia and Hyposplenism

The presence of Howell-Jolly bodies in a blood film may be a clue to the presence of unrecognised asplenia or hyposplenism.  Other investigations that may be of assistance in suspected cases are imaging studies such as ultrasound or CT.

Prevention of Infection

Evidence suggests it is possible to significantly decrease the incidence of infection in asplenic and or hyposplenic patients. Spleen Australia has recently demonstrated a 69% reduction in serious infections in patients on their registry.2 The key strategies utilised by Spleen Australia include; 1. Education
  • Informing patients and their families of the risk of infection, signs and symptoms of sepsis and the need to develop a management plan should these occur:
    • Importance of seeking urgent medical attention if symptomatic.
    • Maintaining a standby supply of antibiotics for emergency use.
  • Provision of advice regarding travel and other potential exposure risks e.g. animal contact.
  • Encouraging the wearing of a Medical Alert bracelet.
2.  Provision of advice regarding appropriate antibiotic therapy (as per Therapeutic Guidelines)
  • Consider antibiotic prophylaxis, particular in first three years post-splenectomy (With either penicillin or roxithromycin).
  • Maintain a standby emergency supply of antibiotics in case of sepsis (usually Amoxil 3g).
3.  Provision of current, detailed, practical guidelines for vaccination (As per Immunisation Handbook)
  • Pneumococcal, Meningococcal, Haemophilus influenza type B vaccines - initial course and ongoing boosters as required.
  • Annual influenza vaccine - to minimise the chance of post-influenza bacterial infection.
Currently, persons resident in Victoria, Queensland and Tasmania are able to register with Spleen Australia and will then receive regular newsletters and reminders when vaccines are due. It is hoped that this service will be extended to other states. See www.spleen.org.au for details.  

Key Messages

  • Infection is a significant, life-long risk in asplenic and hyposplenic patients.
  • The risks can be mitigated by:
    • The early recognition of the underlying condition,
    • Comprehensive patient education,
    • Appropriate use of use of prophylactic and empirical antibiotics, and
    • Ensuring that patients receive recommended initial and ongoing vaccinations.
Spleen Australia provides an excellent range of resources and is happy to assist in the management of these patients if required.  

References

  1. Spleen Australia. Welcome to Spleen Australia: a clinical service and registry for people with a non-functioning spleen. Melbourne VIC: Diabetes Australia. Available from: www.spleen.org.au
  2. Arnott A, Jones P, Franklin LJ, Spelman D, Leder K, Cheng AC. A Registry for Patients With Asplenia/Hyposplenism Reduces the Risk of Infections With Encapsulated Organisms. Clin Infect Dis. 2018 Aug 1; 67(4): 557-61. Available from: https://doi.org/10.1093/cid/ciy141
  General Practice Pathology is a new 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 Alistair McGregor, Sullivan Nicolaides Pathology
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Dr Linda Calabresi
  • Clinical Articles

The Vit D Story Now a Fairytale

It wasn’t that long ago that vitamin D appeared to be the panacea for everything from preventing MS to reducing the risk of diabetes. But the one area where we thought the benefit of this vitamin was not up for debate was bone health. It has been proven - lack of vitamin D causes rickets. It has been proven that vitamin D is important in bone metabolism and turnover. And it has been proven the people with low bone density are more likely to experience fractures. Therefore add vitamin D and improve bones, right? Wrong! The latest meta-analysis of more than 80 randomised controlled trials shows that vitamin D supplementation does not prevent fractures or falls, and does not have any consistently clinically relevant effects on bone mineral density. This comes as a bit of a surprise, to say the least. According to the systematic review, vitamin D had no effect on total fractures, hip fractures, or falls among the 53,000 participants in the pooled analysis. And it didn’t matter if higher or lower doses of vitamin D were used, the New Zealand researchers reported in The Lancet. In looking for a reason for the lack of an effect from supplementation, previous explanations such as baseline 25OHD of trial participants being too high, or the supplement dose being too low, or the trial being done in the wrong population just don’t hold water. The sheer number and variety of trials included in this meta-analysis has meant all of these possible confounders have been accounted for. “The trials we included have a broad range of study designs and populations, but there are consistently neutral results for all endpoints, including the surrogate endpoint of bone mineral density,” they said. Consequently, the researchers said future trials were unlikely to alter these conclusions. “There is little justification to use Vitamin D supplements to maintain or improve musculoskeletal health,” they stated. And while they acknowledge the clear exception to this is in the case of the prevention or treatment of rickets and osteomalacia, in general clinical guidelines should not be recommending vitamin D supplementation for bone health. The conclusion appears quite emphatic and definitive, and it is supported in an accompanying commentary by a leading US endocrinologist. “The authors should be complimented on an important updated analysis on musculoskeletal health,” said Dr Chris Gallagher from Creighton University Medical Centre, Omaha in the US. But he suggests many Vitamin D supporters will still be flying the flag for supplementation, pointing to the multiple potential non-bony benefits. “Within three years, we might have that answer because there are approximately 100,000 participants currently enrolled in randomised, placebo-controlled trials of vitamin D supplementation,” he said. “I look forward to those studies giving us the last word on vitamin D.”  

References

Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018 Oct 4. Available from: http://dx.doi.org/10.1016/S2213-8587(18)30265-1 [epub ahead of print] Gallagher JC. Vitamin D and bone density, fractures, and falls: the end of the story? Lancet Diabetes Endocrinol. 2018 Oct 4. Available from: http://dx.doi.org/10.1016/S2213-8587(18)30269-9 [epub ahead of print]
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

The Gut Microbiome – Fad or The Future?

Which bacteria are colonising your gut is becoming increasingly important, Australian researchers say. More and more evidence is suggesting the gut microbiota has a significant role in both the cause and the cure of a wide range of gastrointestinal and hepatic diseases and conditions. According to a review in The Medical Journal of Australia, research shows that particular types of bacteria colonising the gut have been associated the development of inflammatory bowel disease (IBD), metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), obesity and diabetes. We know that the bowel starts to be colonised by bacteria in utero. The make-up of an individual’s gut microbiota then depends on factors such as mode of delivery, breast-feeding, diet, illness and exposure to antibiotics. By the age of three, the gut microbiota resembles that of an adult. Observational studies have suggested a strong association between alterations in the microbiota because of environmental factors, and an increased risk of diseases. For instance, IBD was very rare in traditional Chinese populations, but studies have shown exposure to Western diets and medicines from a young age has increased the prevalence of this disease. “Asian adults who migrate from countries of low prevalence to countries of high prevalence do not have an increased risk of developing IBD, but their children experience the IBD incidence of their new country of residence,” the review authors said. Stronger evidence comes from studies into the exact nature of bacteria colonising the gut. It appears both the specific bacteria and the diversity of bacteria are important in disease pathogenesis. “For example, the presence of Proteus species at the time of Crohn’s disease resection is associated with early disease recurrence, while the presence of Faecalibacterium prauznitzii is protective against recurrence,” they said. Researchers have also found significant differences in the microbiota of people who develop severe alcoholic hepatitis and those who maintain normal hepatic function despite drinking the same amount of alcohol. Most importantly in the investigation of the role of the gut microbiota, is the emerging evidence that by altering the bacterial colonies in the gut we can alter the course of the disease. The classic example of this, of course, was the discovery of Helicobacter Pylori as the cause of peptic ulcer disease with treatment of this, dramatically changing health outcomes. But since then a lot of the research focus has been on faecal microbiota transplants (or poo transplants as they are commonly known). Mice studies have shown that a mouse will become fat if given a transplant of faecal bacteria from a fat donor mouse. Similarly, a similar result has been shown in a single trial of FMT from lean to obese humans, lowering triglyceride levels and increasing insulin sensitivity. FMT has also been shown to be an effective therapy for recurrent C.difficile infection and in active ulcerative colitis. And while the application of FMT as a treatment continues to be explored, investigators are also looking at how the microbiota can be changed through dietary means and how this can be used therapeutically. While probiotics have not been shown to be effective in the majority of inflammatory diseases, an anti-inflammatory diet combined with liquid formulated enteral nutrition has shown some success in Crohn’s disease. In short, the review authors suggest that the current interest in the gut microbiome is justified and has the potential to provide important therapeutic options in the future. “Microbial manipulation is an effective therapy, likely to have broadening implications,” they concluded.   Reference White LS, Van den Bogaerde J & Kamm M. The gut microbiota: cause and cure of gut diseases. Med J Aust. 2018 Oct 1; 209(7): 312-16. Available from: https://www.mja.com.au/journal/2018/209/7/gut-microbiota-cause-and-cure-gut-diseases doi: 10.5694/mja17.01067

By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Vaccinating the Immunosuppressed – Who, What and When

Vaccination in immunosuppressed adult patients has many facets and can be challenging for GPs who don’t deal with these cases regularly. But there are a few key considerations that can help guide clinicians, says Associate Professor Michael Woodward, Melbourne-based geriatrician, writer, researcher and passionate advocate for health promotion. Firstly, not all immunosuppression is equal. It is important to ascertain the degree of immunosuppression, as some people may be being unnecessarily denied vaccines because they are taking medication that can suppress the immune system but only at higher doses or in different formulations. “For instance, someone who is on inhaled corticosteroids for their asthma or on low dose (less than 20mg) prednisolone daily for just a few weeks is not significantly immunosuppressed and can be vaccinated in the same way as other people,” said Professor Woodward in an interview following his presentation at Healthed’s recent Annual Women's and Children’s Health Update in Perth. However, those on higher doses of steroids or on steroids more long-term, as well as those people who have conditions associated with immunosuppression such as haematological malignancy do need special consideration when it comes to vaccination. Most importantly, live vaccines are not to be given to this group. This includes the new herpes zoster vaccine (Zostavax), which absolutely contraindicated in severely immunocompromised patients. The consequences of inadvertently administering this vaccine to an immunosuppressed patient hit the headlines some months ago, highlighting the importance of this guideline. The other question often asked is whether patients who are known to be immunosuppressed, and therefore at greater risk of significant infections actually need more or stronger doses of the vaccines they are able to have. In some cases that is a very real and worthwhile consideration if you want to achieve the objective of immunoprotection, Professor Woodward said. For example, you might consider giving an immunosuppressed patient the pneumococcal vaccine (Prevenar 13) as opposed to the polysaccharide pneumococcal vaccine (Pneumovax 23). “The conjugate vaccine is generally slightly more likely to produce an immune response [than the polysaccharide vaccine],” he said. The other scenario where GPs might need to be considering vaccination in association with immunosuppression, is in patients who are scheduled for an elective splenectomy. The lack of a spleen is known to be associated with a reduction of the body’s ability to respond to a vaccine, so it is currently recommended that people who are about to undergo a splenectomy have the influenza, pneumococcal and the newer zoster vaccine. In addition, they should be vaccinated against H. influenza B and receive the two meningococcal vaccines currently available. All these are detailed as part of the pre-splenectomy recommendations on the spleen.org.au website, with the exception of the zoster vaccine, as the guidelines have yet to be updated. However, Professor Woodward says most health professionals in this area are advocating the inclusion of the zoster vaccine. Some of these vaccinations may also be given shortly after the removal of the spleen in cases where the splenectomy has been urgent, but this is generally not the remit of the GP. In general, the question of vaccination in the immunosuppressed patient can be complicated. It is a highly specialised area and Professor Woodward suggested, if in doubt GPs might want to seek input from a specialist in this area such as an immunologist or a rheumatologist.

By Dr Linda Calabresi
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Sullivan Nicolaides Pathology
  • Clinical Articles

Prenatal Screening for Chromosome Disorders

Prenatal screening for chromosome disorders by maternal serum screening, ultrasound and non-invasive prenatal tests, such as Harmony®, is an established part of reproductive care in Australia. The overall risk of chromosome disorders rises markedly with maternal age, as shown in Figure 1. (There are two exceptions: Monosomy X, also known as Turner syndrome, and microdeletions, such as 22q11.2, occur independently of maternal age). This does not mean that chromosome screening should be restricted to older mothers. Younger mothers have more babies than older mothers, and the overall outcome is that the majority of pregnancies with a serious chromosome disorder occur in mothers under 35 years of age. For this reason, screening for chromosome disorders in pregnancy should be offered to mothers of all ages. The great majority of these chromosome disorders are new abnormalities that have happened for the first time in this pregnancy. They are not inherited disorders, and genetic testing of the parents provides no information about the risk of such an abnormality. This provides another reason for offering screening for chromosome disorders to all mothers, irrespective of family history.  

The frequency of single-gene disorders at birth

Chromosome disorders are not the only type of genetic condition which can affect the developing foetus. Many serious childhood disorders are due to recessive mutations that have been inherited from parents, with the parents being unaffected by these mutations. A parent who is a carrier of a recessive mutation, that is, having one normal and one abnormal copy of a gene, will not be affected by the abnormal gene. Everyone is a carrier for one or more disorders; this is of no immediate consequence and there usually is no family history of the disorder. The situation changes if both parents are carriers of mutations in the same gene located on one of the autosomes (chromosomes 1-22). The chance of their child inheriting the abnormal gene from each parent, and so developing an autosomal recessive disorder, is 25%. The situation is a little different for a woman with a recessive mutation on an X-chromosome: each of her sons is at 50% risk of inheriting the abnormal gene and being affected, and half of her daughters will be carriers. Overall, the risk of a woman who is an X-linked carrier having an affected child is approximately 25%. There are hundreds of inherited autosomal and X-linked recessive disorders that present in infancy and early childhood. These disorders are individually rare but, together, they are more common than the chromosome disorders for which prenatal screening is widely available and accepted. Further, the risk of these recessive disorders does not vary with maternal age (Figure 1). For mothers under 35 years of age, the risk of having a child with a serious childhood-onset recessive disorder is greater than the risk of having a child with a chromosome disorder.  

Screening potential parents for recessive disorders

These disorders are inherited but there is usually no family history to provide a clue. Until recently, the only way of identifying a carrier of a rare recessive disorder was to diagnose the disorder in their affected child. This has now changed. It is possible to screen a couple for mutations in autosomal genes, and a woman for mutations in X-linked genes, to determine whether they are at 25% risk of having an affected child. This screening test is called ’reproductive carrier screening’. From both a technical and clinical perspective, the challenge lies in choosing which genes to analyse. A number of providers, including Sonic Genetics, offer reproductive carrier screening for mutations responsible for three common disorders: cystic fibrosis and spinal muscular atrophy (both autosomal recessive) and Fragile X syndrome (X-linked recessive). Approximately 6% of people are carriers of one or more of these conditions, and 0.6% (one in 160) couples are at 25% risk of having an affected child. Those couples who are identified as carriers can consider a variety of options, including IVF with a donor gamete, pre-implantation genetic diagnosis, prenatal diagnosis by CVS, or they may make an informed decision to accept the risk. RANZCOG recommends that couples be offered such screening. The cost of this three-gene panel is approximately $400* per person. There is no Medicare rebate for carrier screening; there are exceptions (and restrictions) for people with a documented family history of cystic fibrosis or Fragile X syndrome.  

Expanded reproductive screening

If we were to screen more genes, we would identify more carriers. Sonic Genetics offers a screen of over 300 genes (autosomal and X-linked) which cause serious recessive childhood disorders. We estimate that approximately 70% of Australians are carriers for one or more conditions included in this screen and 3% (one in 30) couples are at 25% risk of having an affected child. This amounts to five times more information than is provided by the three-gene panel. This screen, the Beacon Expanded Carrier Screen, currently costs $995* per person or $1,750* for couples tested together. It is tempting to think that ‘more genes tested = more information for a couple’. This is not the case because the information provided by a carrier screen is also determined by the carrier frequency, mode of inheritance and detection rate of the assay for each gene. Some currently available screens of more than 100 genes provide less information than the three-gene screen described earlier.  

Implementing reproductive screening

Before offering reproductive carrier screening to your patients, it is important to consider some of the nuances, particularly in relation to the Fragile X syndrome (some carriers will develop premature ovarian failure or a tremor/ataxia syndrome in later life) and when there is a family history of a recessive disorder (seek expert advice; do not rely on screening). It is also important to recognise that some couples will not want this carrier information – and others will demand it. Each person needs to be free to make their own decision about what information they wish to have. We provide information about the three-gene and Beacon screens for both requestors and patients on our website. Sonic Genetics also offers genetic counselling free-of-charge for couples who are identified by either of these reproductive carrier screens as being at high risk of having an affected child (see www.sonicgenetics.com.au/rcs/gc).  

Conclusion

It is accepted practice that every woman is offered screening for chromosome disorders in pregnancy, irrespective of age and family history. In a similar vein, every couple should be offered reproductive carrier screening for recessive disorders, irrespective of age and family history. For women under 35 years, the risk of their child having a recessive disorder is greater than the risk of a chromosome disorder. Offering reproductive carrier screening simply represents good medical practice.  

References

RANZCOG. Prenatal screening and diagnostic testing for fetal chromosomal and genetic conditions. 2018 Aug. 35 p. Available from: https://www.ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Prenatal-screening.pdf?ext=.pdf Archibald AD, Smith MJ, Burgess T, Scarff KL, Elliott J, Hunt CE, et al. Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12,000 tests. Genet Med. 2018; 20(5): 513-523 Available from https://www.ncbi.nlm.nih.gov/pubmed/29261177 doi:10.1038/gim.2017.134. Sonic Genetics [Internet]. c2015. Reproductive Carrier Screening; 2018. Available from: www.sonicgenetics.com.au/rcs   General Practice Pathology is a new 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 Sullivan Nicolaides Pathology
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Dr Linda Calabresi
  • Clinical Articles

Detecting Liver Cancer Early

GPs can make a significant difference in curbing the rising rates of liver cancer deaths in Australia, experts say. According to an analysis of over 270 cases of newly diagnosed cases of hepatocellular cancer presenting at seven Melbourne tertiary hospitals over one year, researchers say survival rates could be improved with earlier diagnosis of cirrhosis and better adherence to recommended screening  schedules among those known to be at high risk. “[T]he number of liver cancer-related deaths has been the most rapid for any cancer type in Australia over the past 40 years,” the study authors said in the MJA. And of all the types of liver cancer, hepatocellular carcinoma is by far the most common, accounting for 82%. Even though treatments are available, both curative and palliative survival remains very poor with the Australian 12-month survival rate estimated to be only 62%. In this particular study, conducted over 2012/2013 the mean survival was only 18 months. As one would expect, the patients who did better, who generally survived the longest were those whose tumours were detected at an earlier stage. These were usually the patients who were known to be at high risk of developing liver cancer and were participating in a surveillance program. But this was only 40% of the 272 cases, even though 89% would have qualified for surveillance based on their risk factors. Why was this? Well firstly, many of these people did not know they were at risk. And that’s where GPs fit in. In the study the most common risk factors for liver cancer were found to be hepatitis C infection (41%), alcohol-related liver disease (39%), hepatitis B infection (22%) and non-alcoholic fatty liver disease (14%). Many had more than one risk factor. Most telling was the finding that, even though the vast majority of patients (83%) had cirrhosis when they were diagnosed with hepatocellular carcinoma, for one third of them that was the first they knew of it. The study authors suggest clinicians need to be alert for risk factors for chronic liver disease such as excess alcohol use, chronic HCV and HBV infections and even non-alcoholic liver disease in certain groups. In these people, checking for cirrhosis is likely to be worthwhile. “An aspartate transaminase to platelet ratio index (APRI) value greater than 1.0 predicts cirrhosis with 76% sensitivity and 72% specificity, and the test is simple to undertake,” the researchers said. The other major barrier to the earlier detection of liver cancer identified in the study was the poor adherence to surveillance among those people identified as being at high risk. Researchers found patients with alcohol-related liver disease or decompensated liver disease were the least likely to get regular monitoring. A surveillance program for this particular cancer involves a 6-monthly liver ultrasound and serum alpha-fetoprotein assessment. The study authors are advocating a national hepatocellular cancer surveillance program for those who are at high risk of developing the disease, which would include all patients with cirrhosis, Asian men over 40, women over 50, Africans over 20 years of age, and patients with a family history of [hepatocellular carcinoma] without cirrhosis but with chronic HBV infections. A national program to screen for hepatocellular carcinoma amongst this particular group would be worthwhile, the researchers said, as the incidence of the cancer is high, the screening is non-invasive and inexpensive and, perhaps most importantly early detection has been shown to improve survival. However, until such a national program is developed, researchers are encouraging GPs to ensure that their at-risk patients are enrolled in a surveillance program in order to hopefully improve their health outcomes.   Reference: Hong TP, Gow PJ, Fink M, Dev A, Roberts SK, Nicoll A, et al. Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study. Med J Aust [Internet]. 2018 Sep 24; 209(8): 1-7. Available from: https://www.mja.com.au/journal/2018/209/8/surveillance-improves-survival-patients-hepatocellular-carcinoma-prospective doi: 10.5694/mja18.00373

By Dr Linda Calabresi
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Kevin Davies, Jessica Eccles & Neil Harrison
  • Clinical Articles

What Causes Fibromyalgia?

Fibromyalgia is something of a mystery. It can’t be detected with scans or blood tests, yet it causes lifelong pain for millions of people. The disease mainly affects women (about 75-90% of cases), causing pain all over the body. Because not all healthcare professionals are adept at identifying and diagnosing fibromyalgia, reported rates of the condition vary greatly from country to country. In China, it affects only 0.8% of people, in France around 1.5%, in Canada 3.3%, and in Turkey 8.8%. Estimates in the US range from 2.2% to 6.4%, and in Russia, about 2% of the population is affected. People with the condition are often diagnosed if they have longstanding muscle pain, bone or joint pain and fatigue. Fibromyalgia can also cause insomnia, “brain fog”, some symptoms of depression or anxiety, as well as a range of other complaints, including irritable bowel syndrome and headache. Many patients are also hypermobile (“double-jointed”), and there is some overlap with chronic fatigue syndrome (also known as ME). Guidelines from the American College of Rheumatology make it clear that the diagnosis should be made using defined criteria based on the “widespread pain index” (which scores the number of painful regions out of 19) coupled with a symptom severity scale. The diagnosis also takes fatigue, generalised pain, unrefreshing sleep and cognitive symptoms into account. It doesn’t matter if the patient has another rheumatic disease, they can still be diagnosed with fibromyalgia. The scoring system, recommended by the American College of Rheumatology, is often used in clinical trials, but in the clinic, most doctors rely on detecting tender points in specific places and on excluding other medical conditions, including rheumatic conditions. Unlike say, rheumatoid arthritis or lupus, the tests do not show clear evidence of inflammation or autoimmunity (when the body’s immune system attacks itself) and scans are normal. The lack of inflammation or structural abnormality in muscles or joints – aside from making diagnosis difficult – is the main reason there are no widely accepted or effective treatments. In rheumatic diseases, where we understand the mechanisms that underlie the condition, we have the most effective treatments. In rheumatoid arthritis, for example, we know that much of the inflammation is caused by a cell-signalling protein (cytokine) called tumour necrosis factor and that blocking the activity of this protein switches off the disease in most patients. A number of possible mechanisms have been proposed in fibromyalgia, including abnormal muscle metabolism, reduced levels of steroid hormones such as cortisol, or abnormal small nerve fibres. But these abnormalities aren’t found in all patients with the condition. As such, they can’t be used as part of a diagnostic test, nor can they help develop treatments. Some experts have suggested that fibromyalgia may be related to abnormalities in the autonomic nervous system – the part of the nervous system that controls bodily functions, such as heart rate and blood pressure – and how the brain responds to pain signals and reacts to external stressors (such as infections). But there is currently no hard evidence to back up this theory. Looking for clues To fill in some of the gaps in our knowledge about this devastating condition, our research team at Brighton and Sussex Medical School is investigating the potential role of the autonomic nervous system and inflammation in fibromyalgia and chronic fatigue syndrome. For our study, we have two groups of patients: one with pain as the main symptom and the other with fatigue as the main symptom. We also have matched controls – people without the disease, but otherwise similar characteristics – to make meaningful comparisons. The study is in two parts. First, we will test the patients’ autonomic nervous system using a tilt-table. This involves tilting the person head downwards to see how well their body adapts to this change in posture by changing heart rate and blood pressure (both of which are monitored during the test).Second, we will stimulate patients’ immune systems with a typhoid vaccine (the normal type used in travellers) and perform magnetic resonance brain scans to look for changes in blood flow and also measure the levels of “inflammatory mediators” (the chemicals the body produces in response to stimuli of this type), to see whether these are higher in the fibromyalgia patients. Our study should, for the first time, help us to address the question of whether there really is an abnormal brain response to inflammation or infection in these patient groups and enable us to explore the relationship between the abnormal functioning of the autonomic nervous system and fibromyalgia and chronic fatigue syndrome. Fibromyalgia rarely goes away and treatment options are limited. Only by developing a proper understanding of the disease processes underlying this condition will doctors be able to make a clear, positive diagnosis, and most importantly, offer effective therapy.   Disclosure Statement Kevin Davies receives funding from AR-UK. Jessica Eccles receives funding from Academy of Medical Sciences, National Institute of Health Research, MQ Neil Harrison receives funding from the Wellcome Trust, Medical Research Council (MRC), Arthritis Research UK, and Janssen Pharmaceuticals.

By Kevin Davies, Jessica Eccles & Neil Harrison
shutterstock_305164379
Dr Linda Calabresi
  • Clinical Articles

Fatty Acids of Value in Anxiety

The value of omega-3 fatty acids has come under fire lately. But now a new systematic review suggests they might have benefits beyond the previous therapeutic targets of depression, cardiac health, eye health and arthritis. Researchers have found that omega-3 polyunsaturated fatty acids (PUFA) might reduce the symptoms of clinical anxiety, particularly among those people who had a specific clinical condition be it medical (such as Parkinson disease) or psychological (premenstrual syndrome). “This systematic review…provides the first meta-analytic evidence, to our knowledge, that omega-3 PUFA treatment may be associated with anxiety reduction, which might not only be due to a potential placebo effect, but also from some associations of treatment with reduced anxiety symptoms,” the review authors said in JAMA. The finding is likely to be welcome news for patients with this condition. Be it the potential side-effects of medications or the cost and accessibility of psychological therapy, patients with anxiety, especially those with comorbid medical conditions are keen for alternative or at least supplementary safe, evidence-based treatments for their symptoms. Previous research, in both human and animal studies had found that a lack of omega-3 PUFAs could induce various behavioural and neuropsychiatric disorders. What had not been shown was whether taking this supplement was effective in reducing the specific anxiety symptoms. The review involved an extensive literature search through a wide range of databases including PubMed and Cochrane looking for trials that had assessed the anxiolytic effects of these fatty acids in humans. In the end they found 19 trials that matched their eligibility criteria, which allowed researchers to analyse the effect of supplementation in just over 1200 participants and compare it with about 1000 matched controls who didn’t take the fatty acids. Overall, they found ‘there was a significantly better association of treatment with reduced anxiety symptoms in patients receiving omega-3 PUFA treatment than in those not receiving it.’ Subgroup analysis also showed that those taking at least 2000mg or more of the omega-3 PUFA treatment were more likely to have reduced anxiety. And somewhat surprisingly, those patients receiving supplements containing less than 60% EPA did better than those taking formulations with a greater concentration of EPA. The studies in the review included very different cohorts, and because of this and the limited number of studies included, the authors understandably say the results need to be interpreted with caution. However, while bigger, better studies are still needed to prove the benefit of omega-3 PUFAs in patients with clinical anxiety, this research certainly does suggest that higher dose formulations of less than 60% concentration of EPA might have a role as at least adjunctive treatment to standard therapy.   Reference: Su KP, Tseng PT, Lin PY, Okubo R, Chen TY, Chen YW, et al. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms; A Systematic Review and Meta-analysis. JAMA Network Open [Internet]. 2018 Sep; 1(5): e182327. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.2327.

By Dr Linda Calabresi
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Megan Lee & Joanne Bradbury
  • Clinical Articles

Five Types of Food to Increase Your Psychological Well-Being

We all know eating “healthy” food is good for our physical health and can decrease our risk of developing diabetes, cancer, obesity and heart disease. What is not as well known is that eating healthy food is also good for our mental health and can decrease our risk of depression and anxiety. Mental health disorders are increasing at an alarming rate and therapies and medications cost $US2.5 trillion dollars a year globally. There is now evidence dietary changes can decrease the development of mental health issues and alleviate this growing burden. Australia’s clinical guidelines recommend addressing diet when treating depression. Recently there have been major advances addressing the influence certain foods have on psychological well-being. Increasing these nutrients could not only increase personal well-being but could also decrease the cost of mental health issues all around the world. 1. Complex carbohydrates One way to increase psychological well-being is by fuelling brain cells correctly through the carbohydrates in our food. Complex carbohydrates are sugars made up of large molecules contained within fibre and starch. They are found in fruit, vegetables, and wholegrains and are beneficial for brain health as they release glucose slowly into our system. This helps stabilise our mood. Simple carbohydrates found in sugary snacks and drinks create sugar highs and lows that rapidly increase and decrease feelings of happiness and produce a negative effect on our psychological well-being. We often use these types of sugary foods to comfort us when we’re feeling down. But this can create an addiction-like response in the brain, similar to illicit drugs that increase mood for the short term but have negative long-term effects. Increasing intake of complex carbohydrates and decreasing sugary drinks and snacks could be the first step in increased happiness and well-being. 2. Antioxidants Oxidation is a normal process our cells carry out to function. Oxidation produces energy for our body and brain. Unfortunately, this process also creates oxidative stress and more of this happens in the brain than any other part of the body. Chemicals that promote happiness in the brain such as dopamine and serotonin are reduced due to oxidation and this can contribute to a decrease in mental health. Antioxidants found in brightly coloured foods such as fruit and vegetables act as a defence against oxidative stress and inflammation in the brain and body. Antioxidants also repair oxidative damage and scavenge free radicals that cause cell damage in the brain. Eating more antioxidant-rich foods can increase the feel-good chemicals in our brain and heighten mood. Antioxidants can help restore the happy chemicals in the brain. www.shutterstock.com.au 3. Omega 3 Omega 3 are polyunsaturated fatty acids that are involved in the process of converting food into energy. They are important for the health of the brain and the communication of its feel-good chemicals dopamine, serotonin and norepinephrine. Omega 3 fatty acids are commonly found in oily fish, nuts, seeds, leafy vegetables, eggs, and in grass fed meats. Omega 3 has been found to increase brain functioning, can slow down the progression of dementia and may improve symptoms of depression. Omega 3 are essential nutrients that are not readily produced by the body and can only be found in the foods we eat, so it’s imperative we include more foods high in omega 3 in our everyday diet. 4. B vitamins B vitamins play a large role in the production of our brain’s happiness chemicals serotonin and dopamine and can be found in green vegetables, beans, bananas, and beetroot. High amounts of vitamins B6, B12, and folate in the diet have been known to protect against depression and too low amounts to increase the severity of symptoms. Vitamin B deficiency can result in a reduced production of happiness chemicals in our brain and can lead to the onset of low mood that could lead to mental health issues over a long period. Increasing B vitamins in our diet could increase the production of the feel good chemicals in our brain which promote happiness and well-being. 5. Prebiotics and probiotics The trillions of good and bad bacteria living in our tummies also influence our mood, behaviour and brain health. Chemical messengers produced in our stomach influence our emotions, appetite and our reactions to stressful situations. Prebiotics and probiotics found in yoghurt, cheese and fermented foods such as kombucha, sauerkraut and kimchi work on the same pathways in the brain as antidepressant medications and studies have found they might have similar effects. Prebiotics and Probiotics have been found to suppress immune reactions in the body, reduce inflammation in the brain, decrease depressed and anxious states and elevate happy emotions. Incorporating these foods into our diet will not only increase our physical health but will have beneficial effects on our mental health, including reducing our risk of disorders such as depression and anxiety.   Disclosure Statement Megan Lee receives funding from Southern Cross University and Santos Organics Joanne Bradbury receives funding from the Australian Traditional-Medicinal Society (ATMS), Santos Organics, and Metagenics to support academic research

By Megan Lee & Joanne Bradbury
The dementia ‘tsunami’ is coming – but two potential medications offer hope
Dr Linda Calabresi
  • Clinical Articles

Predicting and Preventing Dementia

Adolescent boys who struggle to understand how basic machines work and young girls who have difficulty remembering words are at increased risk of developing dementia when they’re older, new research has found. According to the longitudinal study published in The Journal of the American Medical Association, lower mechanical reasoning in adolescence in boys was associated with a 17% higher risk of having dementia when they were 70. With girls it was a lower memory for words in adolescence that increased the odds of developing the degenerative disease. It has been known for some time that the smarter you are throughout life, even as a child the less likely it is that you will develop dementia. Not a guarantee of protection – just a general trend. It has to do with cognitive reserve, the US researchers explain. “Based on the cognitive reserve hypothesis, high levels of cognitive functioning and reserve accumulated throughout the life course may protect against brain pathology and clinical manifestations of dementia,” they wrote. This theory has been supported by a number of studies such as the Scottish Mental Health Survey that showed that lower mental ability at age 11 increased the risk of dementia down the track. But what had been less well-defined was whether there were any particular aspects of intelligence in young people that were better predictors (or protectors) of dementia than others. This study goes some way to addressing this. Researchers were able to link sociobehavioural data collected from high school children back in 1960 with Medicare claims data over 50 years later that identified those people who had been diagnosed with Alzheimer's disease and related disorders. Interestingly, poor adolescent performance in other areas of intelligence such as mathematics and visualisation were also associated with dementia but not nearly to the extent of mechanical reasoning and word memory. So why is this so? The study authors say there are a few possible explanations. Maybe the poor performance in adolescence reflected poor brain development earlier in life, a risk factor for dementia. Or maybe these adolescents are more susceptible to neuropathology as they get older? Or maybe they are the adolescents who adopt poor health behaviours such as smoking and little exercise? “Regardless of mechanism, our findings emphasise that early-life risk stretches across the life course,” they said. And what can be done about it? That’s the million-dollar question. The researchers say the hope is if we know the at-risk group we can get aggressive with preventive management early. “Efforts to promote cognitive reserve-building experiences and positive health behaviours throughout the life course may prevent or delay clinical symptoms of Alzheimer's disease and related disorder.” An accompanying editorial takes this concept a little further. Dr Tom Russ, a Scottish psychiatrist says interventional research has identified a number of factors that can potentially influence cognitive reserve. These include modifiable health factors, education, social support, positive affect, stimulating activities and/or novel experiences, and cognitive training. As Dr Russ says, you can’t necessarily change all of these risk factors, and even the ones you can change may become less modifiable later in life. But as this study demonstrates, you may be able to work on a person’s cognitive reserve at different stages throughout their life to ultimately lower their risk of dementia.   Reference
  1. Huang AR, Strombotne KL, Horner EM, Lapham SJ, Adolescent Cognitive Aptitudes and Later-in-Life Alzheimer Disease and Related Disorders. JAMA Network Open [Internet]. 2018 Sep; 1(5): e181726. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.1726.
  2. Russ TC, Intelligence, Cognitive Reserve, and Dementia: Time for Intervention? JAMA Network Open [Internet]. 2018 Sep; 1(5): e181724. Available from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2701735 doi:10.1001/jamanetworkopen.2018.1724.

By Dr Linda Calabresi
vcacinations in pregnancy
Dr James Harraway
  • Clinical Articles

Fetal Fraction – The Essential Factor in Non-Invasive Prenatal Testing

Non-Invasive Prenatal Testing (NIPT), the cell-free DNA-based blood test that screens for fetal chromosomal abnormalities, is fast becoming a routine part of obstetric care. NIPT at a glance During pregnancy, maternal plasma contains fragments of DNA from the mother and from the placenta (fetal DNA). The proportion of DNA fragments from particular chromosomes is usually very stable throughout pregnancy. If there is an excess of fetal fragments from one chromosome, the proportion of fragments from that chromosome will be changed. Inconclusive tests A key reason that NIPTs should precisely measures the amount of fetal DNA in the sample – the fetal fraction – is if there is insufficient fetal DNA, the result may merely reflect the genetic status of the mother. NIPT assays should report a result only if there is sufficient fetal DNA to be confident of accuracy. Rarely, a test for trisomy 21,18 and 13 cannot be reported. This occurs in 3% of women tested by Sonic Genetics and is usually because there is insufficient fetal DNA compared with maternal DNA in the mother’s plasma. This low fetal fraction can be due to a relative excess of maternal DNA and this can vary over time. It is more common in women with increased body weight, and more likely in the presence of infection and inflammation, or after exercise. It also occurs if the mother or fetus has some subtle benign variations in chromosome structure (copy number variants) that make estimating the proportion of fragments from a chromosome unreliable. In some instances, the DNA in the sample has degraded during collection and shipping to the laboratory, and the quality is insufficient for a reliable result. These factors interfere with quality control of the test. Two thirds of women will get a result on re-testing. However, if the second test is inconclusive, it should not be repeated. This occurs in 1% of pregnant women screened. It is also not worth using another form of non-invasive prenatal test. Other tests do not estimate the fetal fraction accurately and may provide false reassurance. A decision about other test modalities (combined first trimester screen, second trimester serum screen, detailed ultrasonography or invasive genetic testing such as CVS/amniocentesis) should be based on assessment of all identified risk factors and may require specialist consultation. More rarely (in 0.5 –1% of women) the test reports a result for trisomy 21, 18 and 13 but not for fetal gender and sex chromosome abnormalities. It is unlikely that a repeat test will provide a result. A decision about using fetal ultrasound or invasive genetic testing to document fetal gender should be based on assessment of need and any identified risk factors.   General Practice Pathology is a new 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 James Harraway, Sullivan Nicolaides Pathology

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