Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 24th March 2016 (#35)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
None
Must Read Articles
CLINICAL PRACTICE
Chronic
Stable Angina
Management
of angina includes lifestyle changes and pharmacologic treatment to reduce
cardiovascular risks, antianginal therapies (beta-blockers, long-acting
nitrates, calcium-channel blockers, and — recently in the United States —
ranolazine), and revascularization.
This is an excellent Clinical Practice article
outlining the management of a patient with chronic stable angina. Current
therapies are well outlined together with the relevant updated literature. Of
interest are the emerging therapies for angina, such as ranolazine and less
frequently used ivabradine which students are being exposed to in some Perth
hospitals. Also of note is the future use of allopurinol (recommended in the
European guidelines) which decreases myocardial oxygen demand and improves
endothelial function, as well as limiting urate crystal deposition.
Recommended
learning: Epidemiology of coronary artery disease, pathology,
clinical presentations and management. Review MED300 case on Acute Coronary
Syndrome.
Articles Recommended for Medical Students
Perspective
Lead
Contamination in Flint — An Abject Failure to Protect Public Health
The
recent episode in Flint, Michigan, has brought the issue of lead in water into
the public eye. But the dangers of lead exposure have been recognized for
millennia, and we have the knowledge required to redress this social crime — if
only we had the political will.
Poisoning of the water supply with lead in Flint
Michigan is a tragic, ongoing event that should never have occurred. The
genesis of this illegal act followed the election of a Republican Governor of
Michigan who privatized local elected councils and replaced them with his management
cronies in order to ostensibly save costs at the local city level. Because of
privatization and greedy, inexperienced administrators, the state is now bankrupt.
Diversion of the clean water supply from Lake Huron to the Flint River, to
which was added ferric chloride to reduce formation of trihalomethane
contaminants, resulted in water that was 19 times more corrosive than the
original water. The acidic water dissolved lead from the pipes in homes
resulting in lead poisoning of the population, particularly of the fetuses and
their developing brains and children who drink the water. The population of Flint is poor, disenfranchised and predominantly African-American. What was criminal,
and particularly distressing about this event, was the knowledge of this
contamination by local government, and undoubtedly the governor, 18 months
before it became public. Thanks to a stubborn, caring local pediatrician-public health official treating children with lead poisoning,
this event was made public.
IMAGES IN CLINICAL MEDICINE
Diffuse
Melanosis Cutis
A
76-year-old man was admitted to the hospital because of increasing generalized
weakness. Several weeks earlier, a progressive gray–blue discoloration of the
skin had developed. Because of the pronounced change in skin color, this white
patient was no longer recognizable on his identity card.
The interesting aspect of this rare manifestation of
metastatic melanoma, which heralds a poor prognosis, is the mechanism of the
skin pigmentation. This is not due to malignant cells within the dermis, but
rather the accumulation of melanin and melanosomes, derived from lysed melanoma
cells elsewhere. This pigment then accumulates within dermal mononuclear
phagocytic cells. Do macrophages in the spleen and liver also accumulate
melanin and melanosomes or is this a particular skin tropism?
Recommended
learning: Review the types and causes of diffuse skin pigmentation
EDITORIAL
The
Genetics of Dyslipidemia — When Less Is More
The review summarizes the results of the two papers in
the current issue of the Journal (http://www.nejm.org/doi/full/10.1056/NEJMoa1510926; http://www.nejm.org/doi/full/10.1056/NEJMoa1507652)
which examine the effects of either loss-of function or gain-of-function
mutations in the angiopoietin-like 4 (ANGPTL4) gene on levels of triglycerides
(TGs) and HDL in humans and animals.
The protein ANGPTL4 inhibits lipoprotein lipase (LPL)
whose function it is to break down plasma triglycerides into glycerol and free
fatty acids which are then metabolized by cells (see Figure 2, in http://www.nejm.org/doi/full/10.1056/NEJMoa1507652
p1141). When there was a loss-of-function mutation found in
the ANGPTL4 gene, this resulted in non-functioning ANGPTL4. This resulted in excessive LPL activity and
reduced plasma TGs, elevated HDL levels and reduced clinical coronary artery
disease (CAD). Both studies involved samples from large cohorts of patients
with both CAD and controls (US study and a multinational study) and involved
extensive genetic studies. In the study by Dewey et al., mice and monkeys were also
treated with an inhibiting monoclonal antibody against ANGPTL4 which resulted
in reduced TGs and elevated HDL levels.
These studies provide further evidence that elevated
triglycerides play a role in the pathogenesis of atherosclerosis. Further
exploration of this pathway may provide a possible therapeutic window into the
future.
A
word of caution! A recent presentation at the annual
meeting of the American College of Cardiology gives us pause to reflect and
reminds us that we have a long way to go before we have clinically available more
effective LDL lowering agents than the currently available statins and the
recently available monoclonal antibody against PCSK9 (http://www.nejm.org/doi/full/10.1056/NEJMoa1105803 ).
Evacetrapid, a CETP inhibitor marketed by Eli Lilly and tested in 12,000
patients, reduced LDL levels by 37% and elevated HDL levels by 130% but unexpectedly
had no effect on CV outcomes. This
drug was also associated with an increase in hypertension. The study was
terminated prematurely.
Recommended
learning: Review the common types of hyperlipidaemia associated
with elevated plasma LDL and VLDL levels.
EDITORIAL
Parenteral
Nutrition in Critically Ill Children
ORIGINAL
ARTICLE
Early versus Late Parenteral Nutrition in
Critically Ill Children
In
this multicenter randomized, controlled trial, withholding parenteral nutrition
from critically ill children in the pediatric intensive care unit for 1 week
was clinically superior to providing early parenteral nutrition. Fluid loading
was provided in both groups.
This is an important study which addresses the question
as to when (day 1 or day 8 after admission) parenteral nutrition should be administered
to critically ill ICU children who were receiving insufficient enteral
nutrition (in this three centre study, adequate enteral nutrition was defined
as more than 80% of the nutrient target). The majority of the children were not
malnourished at onset and all had functional GI tracts.
The results indicated that although mortality rates
were similar in both groups, those children who received the later parenteral nutrition
beginning on day 8 had 7.8% fewer new infections, were discharged 2.7 days
earlier from the ICU, had shorter duration on mechanical ventilation, had
shorter hospital stays and were less likely to receive real-replacement therapy.
Any design problems associated with the study are discussed in the Review.
Overall this is a landmark study that will define the standard of care for
the timing of parenteral nutrition in critically ill, non-malnourished children
receiving inadequate enteral nutrition who are admitted to the ICU.
Important Articles Related to Mechanisms of Disease and
Translational Research
None
Other articles which should be of interest to medical students
Perspective
Mitochondrial
Replacement Techniques — Implications for the Clinical Community
An Institute
of Medicine committee concluded that it's ethical to pursue clinical studies of
mitochondrial replacement techniques, under certain conditions, but that
critical safety and efficacy questions remain before regulatory approval or
clinical use can occur.
The Perspective
introduces the fascinating concept of transferring nuclear DNA from the oocyte
(maternal spindle transfer) or the fertilized egg (pronuclear transfer) of a patient
with mutated mitochondrial DNA (mtDNA) into a recipient oocyte or fertilized
egg containing non-mutated mtDNA (methods are well illustrated in the
accompanying Figure). Both methods involve IVF. Potential ethical problems
associated with these techniques are discussed in detail. The Institute of
Medicine has given approval for exploration of this area to treat mothers who
harbour mutated mtDNA in their oocytes.
This technique cannot be used to treat patients with mitochondrial
disease, only the maternal carrier of the mutation. It is estimated that with either the spindle
or pronucleus transfer that up to 2% of mtDNA may be transferred. Some of this mtDNA may contain mutated mtDNA.
However, considering the concept of heteroplasmy of mtDNA, it is predicted that
there will be insufficient mutated mtDNA in the recipient host to result in
clinical disease (the concept of “heteroplasmy shift therapy”).
Recommended
learning: This excellent Perspective
provides the student and teacher a chance to review mitochondrial DNA biology
and the uncommon diseases associated with mutations or deletion of mtDNA.
ORIGINAL ARTICLE
A
Multicenter Observational Study of Incretin-based Drugs and Heart Failure
In
this analysis of data from several large cohorts of patients with diabetes,
antidiabetic incretin-based drugs were not associated with an increased risk of
hospitalization for heart failure, as compared with commonly used combinations
of oral antidiabetic drugs.
An interesting aspect of this multicentre,
retrospective, nested case-control, Canadian study was that most of the data
was mined from US and UK databases. The
study included 1,499,650 patients in the study cohort (Figure 1). Of the patients
without a history of heart failure, 74% of the data was from the US and 9% from
the UK (Table 1). Of those with heart
failure, 58% of the data was from the US and 4% from UK databases.
The study has well demonstrated that in a selected
group of diabetic patients taking only oral hypoglycaemic agents, that
incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) and
glucagon-like peptide 1 (GLP-1) analogues, did not result in an increased
admission rate for heart failure. This applied equally to patients with and
without a pre-existing diagnosis of heart failure. Patients exhibiting heart
failure had a significantly higher frequency of coronary artery disease, previous
coronary revascularization, stroke, myocardial infarction, CKD, and COPD.
Recommended
learning: Review the groups of oral hypoglycaemic drugs used to
treat diabetes mellitus.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
9-2016 — A 29-Year-Old Man with Dyspnea and Chest Pain
A
29-year-old man presented with severe dyspnea and chest pain on the right side.
Computed tomographic angiography revealed a filling defect in the main and
right pulmonary arteries that was consistent with pulmonary embolism.
Diagnostic procedures were performed.
This is an interesting CPC involving a rare
presentation of a common tumour. It also
reviews the possible causes of pulmonary embolic disease in a 29-year-old male.
The important lesson is to not to forget the commonest
non-lymphomatous solid tumour in a male of this age.
Recommended
learning: Review the pathology, clinical presentation,
investigations and management of germ cell and non-germ cell testicular
tumours.
