Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 23rd June 2016 (#48)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
None
Must Read Articles
None
Articles Recommended for Medical Students
REVIEW ARTICLE
Crystallopathies
A
number of diseases are related to the deposition of crystals, misfolded
proteins, or airborne microparticles. These diverse stimuli elicit a host
response that is complex but that shows remarkable similarities among diseases,
which may offer new therapeutic targets.
This is a novel unifying approach which combines
crystals and microparticles into specific groups and coins the new broader term
“cystallopathy (Table 1).”
Crystallopathies are primarily classified into:
1. intrinsic-organic
e.g. bile, cholesterol, amyloid, monosodium urate.
2. intrinsic-inorganic
e.g. calcium pyrophosphate, calcium oxalates, hydroxyapatite.
3. extrinsic
e.g. asbestos, implant debris, tobacco smoke and air pollutants, occupational
dusts.
The review then groups the crystallopathies into the
predominant pathological process each produces (Figure 1) and into the
pathological processes induced, based on their size (Figure 2).
While this may appear somewhat contrived and more
complicated than it should, the most important unifying concept is the
molecular mechanisms whereby crystals lead to necroinflammation (Figure 3),
particularly the NLRP3 inflammasome. The authors then discuss innovative
therapies based on molecular targets.
I recommend time reviewing the glossary of terms,
especially the types of “-osis” (necrosis, apoptosis, pyproptosis, necroptosis,
ferroptosis and NETosis). Many students
will have been introduced to these terms in the pathology lectures on
inflammation. Review the excellent
detailed Tables and Figures.
Recommended
learning:
1. Review
the pathology of acute inflammation.
2. Review
the clinical types of crystal induced arthropathies (urate, pyrophosphate and
hydroxyapatite).
3. Review
the role and structure of the inflammasome.
IMAGES IN CLINICAL MEDICINE
Iododerma
from Contrast Material
A
57-year-old man presented with hematuria. Intravenous urography was performed
after the administration of iodinated contrast material. Several hours later,
generalized pustular eruptions developed, with multiple coalescing vesicles and
pus-filled bullae.
This is a very rare cutaneous reaction to
iodine-containing contrast material associated with neutrophilia, eosinophilia,
and large numbers of neutrophils within the skin.
IMAGES IN CLINICAL MEDICINE
Squamous-Cell
Carcinoma of the Tongue
A
73-year-old woman presented with a persistent ulcer and white patch on the
right margin of the tongue. Intraoral examination revealed a superficial ulcer
with a homogeneous base, an indurated upper border, and an adjacent speckled
red and white patch at the lower border.
This is an excellent clinical picture (view at Full
screen) of an ulcer on the side of the tongue and histologically confirmed to
be a SCC.
Recommended
learning:
1. Review
the clinical examination and investigations of a patient presenting with a solitary
neck mass.
2. Review
the causes of head and neck cancer (mostly SCC), their associations and, in
particular, HPV infection with oropharyngeal cancer.
3. Review
the current status and recommendations for HPV vaccination in Australia.
ORIGINAL ARTICLE
Body-Mass
Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood
In
this study, a range of values for body-mass index that were well within the
accepted normal range in adolescence predicted increased cardiovascular and
all-cause mortality during 40 years of follow-up.
This impressive Israeli study required long-term
commitment and funding with a relatively simple question asked: what effect
does a single BMI reading in adolescence have on the frequency of
cardiovascular death 40 years later?
2.3 million Israelis (female and male) with a mean age
of 17.3 years (range 16 -19 years) were enrolled in the study, which spanned the
period 1967 to 2011. At the onset of the study, the individual BMIs were calculated. In this adolescent population, the initial
BMI range at presentation ranged from 16.7 to 34.1.
The primary outcome was the number of deaths due to
cardiovascular causes (coronary artery disease, stroke and sudden death over
the duration of the study).
2,918 (9.1%) of 32,127 deaths were due to CV disease
with the mean age of cardiovascular death being 45.3 years. 90% of deaths
occurred in males.
The
major messages from the study were:
1. The
cumulative CV mortality for participants with BMIs less than the 50th
percentile (BMIs 21 or less) is similar over the 40-year study period (Figure
2, which is the most informative).
2. For
BMIs exceeding the 50th percentile and over, the CV death rate increased progressively
with increases in the BMI.
3. What
was unexpected was that for BMIs in the range 21.5 - 23 (50% - 74% percentile),
in the accepted normal range, the CV death rate and the all-cause mortality
rate began to significantly rise.
There
are several factors to consider with this study:
1. BMI
was only measured at the onset.
2. There
was no data on smoking, diabetes mellitus, lipids, fitness or exercise.
3. Cause-specific
data was unavailable for 6.8% of deaths.
4. The
current patient population were not followed into older age, when it would be
predicted that the risk of cardiovascular death would significantly increase.
5. While
this data applies to an Israeli population with 85% of participants born in
Israel, the countries of origin of the population studied was not too
dissimilar from that of most advanced Western societies (demographics in Table
1).
6. The
authors indicate that it is impossible to determine if the BMI in adolescence predetermines
the CV mortality or if the initial BMI is a harbinger of a progressive rise in
the BMI over time and it is the latter that sets the patient up for risk
factors of CV death.
What advice do you give adolescents whose BMI is in the
range 50 -74% percentile? Based on the current data, adolescents should be
encouraged to maintain a BMI of less than 23.
ORIGINAL ARTICLE
A
Prospective Study of Sudden Cardiac Death among Children and Young Adults
In
490 cases of sudden cardiac death identified over a 3-year period (annual
incidence of 1.3 per 100,000), causes were found in 60% through conventional
autopsy, and a clinically relevant cardiac gene mutation was found in 27% of
the remaining cases in which genetic testing was performed.
This is a large University of Sydney based study of 198
patients, aged 1 to 35 years, with unexplained cardiac death (40%) gathered
from a total cohort of 490 patients with sudden cardiac death. Patients were
gathered from Australia and New Zealand over 3 years ending in 2012. The most
common cause of explained acute sudden cardiac death was coronary artery disease,
mostly in the 31 to 35-year-old population (24%) and inherited cardiomyopathies
(16%).
Of the 113 patients with unexplained sudden cardiac
death, a clinically relevant cardiac gene mutation was identified in 31 (27%).
A total of at least 59 cardiac genes were examined (Table 2). In 13% of
families, similar abnormal genes were identified therefore allowing genetic
counselling. An excellent Nature review on genetics and channelopathies follows (http://www.nature.com/gim/journal/v12/n5/pdf/gim201044a.pdf)
.This study reinforces the importance of obtaining a detailed history from any
patient with a family history of sudden cardiac death.
Recommended
learning: Review the more common diseases associated with hereditary
and acquired abnormalities in sodium, potassium, calcium, and chloride
channels.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
19-2016 — A 65-Year-Old Man with End-Stage Renal Disease and a Pruritic Rash
A
65-year-old man with end-stage renal disease and a history of syphilis
presented with a leg injury and a diffuse pruritic rash. A recent serologic
test had been positive for human T-lymphotropic virus type 1. A diagnostic
procedure was performed.
This is a patient with end-stage kidney disease who was
referred for renal transplant assessment. He was found to be HTLV-1 positive
and had developed a new onset skin rash. The differential diagnosis of a
pruritic papulo-squamous eruption is discussed in this setting, which included
inflammatory diseases, infectious diseases, and malignancy. I recommend that
medical students read only the DD unless there is a particular interest in this
disorder.
Important Articles Related to Mechanisms of Disease and
Translational Research
CLINICAL IMPLICATIONS OF BASIC RESEARCH
A
Gut Feeling about Thrombosis
Plasma
levels of trimethylamine-N-oxide (TMAO), derived from dietary nutrients, are
associated with atherothrombotic disease. Experiments in mice suggest that the
mechanism involves platelet activation and show that the gastrointestinal
microbiota influence plasma TMAO levels.
This is an interesting and speculative article supports
the old adage “you are what you eat.”
The summary of the data (Figure 1) proposes that
phosphatidylcholine (PC), choline, and carnitine in the diet are converted by
the gut microbiota to trimethylamine (TMA). In the hepatocyte, TMA is converted
to TMAO (TMA-N-oxide). In humans, high serum levels of TMAO are associated with
diets rich in red meat and eggs. High levels of TMAO are associated with
increased cardiovascular events. TMAO modifies cholesterol metabolism and aids
in the conversion of macrophages to foam cells. If patients are treated with
antibiotics, the TMAO level falls. An excellent more detailed discussion is
presented in an earlier editorial from 2013. (http://www.nejm.org/doi/full/10.1056/NEJMe1302154 ).
Overall, the study by Zhu et al Cell, 2016 provides
more evidence that gut microbiota production of TMA and then TMAO by the
hepatocyte leads to increased platelet hypersensitivity by releasing
intracellular calcium, increasing the risk of platelet aggregation and
progression of the atherosclerotic vascular disease.
Other Articles which should interest medical students
Perspective
A
Global, Neutral Platform for Sharing Trial Data
Brigham
and Women's Hospital–Harvard University's Multi-Regional Clinical Trials
Center, along with partners, is designing a platform to link existing
data-sharing platforms and communities and host data from investigators who
want to share data but lack the resources to do so.
The four perspective articles involve handling of data
obtained from clinical trials. They involve collection of data, analysis, platforms,
sharing of data, and patient confidentially. Several initiatives have been
undertaken to enable sharing of clinical trial data to benefit patients,
researchers and funding agencies. Shared data will lead to an increase in
specific data, aid in standardizing protocols and limit unnecessary duplicative
research endeavours.
Two
paragraphs from the perspective articles summarize the relevant information:
“Moral arguments
strongly favor data sharing, especially for data generated using philanthropic
or public resources. But the practical benefits of data sharing are also
compelling. If biomedical researchers continue to share data, the HBGDki (The
Healthy Birth, Growth, and Development Knowledge Integration) and other
knowledge bases can become living repositories that advance the field, fulfill
the goals of the taxpayers and private funders who enabled the work, and honor
the wishes of the participants in the studies. The end result of data sharing,
done properly, will be more knowledge that will help all people lead healthy
and productive lives.” (http://www.nejm.org/doi/full/10.1056/NEJMp1605441).
“Despite emerging requirements that clinical trial data
be made available, as yet there has been no organized effort to coordinate
existing platforms and servers and provide a basic platform to enable most data
generators to share their trial data simply, efficiently, and appropriately and
to enable discovery of patient-level data wherever they reside. Now such an
entity is being created, sponsored by the Multi-Regional Clinical Trials Center
of Brigham and Women’s Hospital and Harvard University (MRCT Center). We are
working with institutional and individual partners to design a data-sharing
platform that we call “Vivli” — meant to recall the Greek “vivlithíki,” or
library, and the Latin “viv,” or life. Vivli will link existing data-sharing
platforms and communities, while hosting data from investigators who aspire to
share data but lack the resources to do so. To establish a platform
expeditiously, we plan to launch Vivli in partnership with existing
data-sharing systems.”
(http://www.nejm.org/doi/full/10.1056/NEJMp1605348)
ORIGINAL ARTICLE
Adapted
Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma
A
randomized trial suggests that patients with negative PET-CT findings after two
cycles of ABVD may have the bleomycin dropped from the regimen for the final
four cycles. The omission of bleomycin reduced pulmonary toxic effects without
reducing overall survival.
EDITORIAL
Fine-Tuning
the Treatment of Hodgkin’s Lymphoma
This study raises the question: how aggressive does
therapy need to be to cure advanced Hodgkin’s lymphoma particularly if the side
effects of therapy are significant? The main therapeutic area of concern in the
standard treatment protocols was bleomycin which can result in acute and
progressive pulmonary injury.
After two cycles of standard ABVD (Adriamycin,
bleomycin, vinblastine, dacarbazine), 1135 patients underwent a PET-CT to
ascertain if residual disease was present. 937 had negative PET-CT scans. Of
these 470 continued on the standard ABVD for a further 4 cycles, while 465 had
four cycles of AVD excluding the bleomycin (Figure 1). In summary, the primary
outcome (3-year progression-free survival) was similar in both groups with less
pulmonary toxicity in the group not receiving bleomycin.
The remaining 172 patients, with a positive PET-CT
after two rounds of ABVD, received more complex chemotherapy with or without
radiation depending on the oncologist’s choice. Of these, the 3-year
progression-free survival was similar to the above groups.
In summary, the use of PET-CT after two cycles of
standard chemotherapy for advanced Hodgkin’s lymphoma was useful in determining
the subsequent treatment protocols which all resulted in similar primary
outcomes.
Recommended
learning: Review the biology, pathology, clinical
presentations, principles of therapy, and overall outcomes in patients with
Hodgkin’s lymphoma.
EDITORIAL
K13-Propeller Mutations and Malaria
Resistance
Currently the major concern in treating falciparum
malaria is the developing drug resistance to artemisinin which is the major and
most effective drug. This drug, isolated from the sweet wormwood plant, had
been used by the Chinese for over 4000 years to treat malaria. It is now
synthesised in yeast.
The mechanism for this drug resistance is the
development of the K13-propeller mutation in the malarial parasite. Patient
samples from 59 countries with endemic falciparum malaria were studied for the
K-13 mutation. Fortunately, this was found
only in Plasmodium falciparum in South-East Asia and China, not sub-Saharan
Africa. Artemisinin not only clears the disease forming asexual blood stages,
but also kills the gametocytes which are responsible for disease transmission.
Thus, it is an extremely valuable drug and the development of drug resistance
in sub-Saharan Africa would be a public health disaster.
