Richard Lehman’s journal review—6 March 2017

Richard Lehman reviews the latest research in the leading medical journals.

richard_lehmanNEJM  2 Mar 2017  Vol 376

“Subclinical hypothyroidism” in pregnancy

Observational studies have shown an association between high levels of thyroid stimulating hormone (TSH, or thyrotropin) or low levels of free thyroxine (T4) or both in mothers and lowered measures of intelligence in their children. As so often happens, guidelines ran ahead of the evidence, and recommended screening long before there was evidence that treatment with levothyroxine would make any difference. Now comes the trial evidence, and it’s negative. In this context, “subclinical hypothyroidism” is the name given to a high TSH level accompanied by a normal circulating T4 level, whereas a low circulating T4 level is called hypothyroxinaemia. Bear in mind that both are defined by arbitrary cut-off points in continuously distributed biochemical variables, occurring in people without symptoms. For this reason and more than I have space to mention, I’m not surprised that “Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions.”

Itching to try nemolizumab?

Nemolizumab is a humanized monoclonal antibody against interleukin-31 receptor A which binds to interleukin-31 receptor A on a number of cells, including neurons, to inhibit interleukin-31 signalling. This signalling causes the sensation of itching, so nemolizumab is designed to reduce itching, not to cure the cause of the itching. It’s as well to make this clear, since in this phase 2 trial in people with eczema, it did not significantly reduce the eczema, whereas it did reduce itching. Like most such phase 2 trial reports in leading journals, this one is written by academic and industry authors with the help of a hired writing agency, and its results are the subject of confidentiality agreements between the authors and Chugai Pharmaceutical. The trial lasted 12 weeks and tell us nothing about the long-term harms or benefits of this product. But what I’m itching to find out is the price.

Genes to hammer sickle

I can’t say that I’ve ever marched under a Communist banner before, but there were lots at the NHS march on Saturday and one even brushed my head. Like hammers and sickles themselves, they are symbols of the past; though in a world where eight individuals own half the world’s wealth, Lenin in his mausoleum must be muttering “You can’t say I didn’t warn you!” Anyway, when doctors talk about sickles, it tends to be about sickle cell disease, a heritable blood disorder which few thought science could ever hammer. But here from Paris is the first report of successful gene therapy for sickle cell disease. A boy with the βSS genotype, a single 3.7-kb α-globin gene deletion, was going through hell. He had a history of numerous agonizing vaso-occlusive crises, two episodes of the acute chest syndrome, and bilateral hip osteonecrosis. He had undergone cholecystectomy and splenectomy. Now what? His only hope was that someone would come up with a way of stopping his haemoglobin S forming polymers that blocked his small blood vessels. Using a lentivirus, the boffins of Paris succeeded in introducing an antisickling gene into his blood stem cells. The goal was to achieve effective, persistent inhibition of polymerization of haemoglobin S. So far, it’s looking good: fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like–globin chains) without recurrence of sickle crises. As for Lenin, he must be lying there asking “But how many people with sickle cell disease will be able to afford this?”

JAMA  28 Feb 2017 Vol 317

Later cancers in childhood cancer survivors

It will be hard for some of you to believe this, but when I first started writing these reviews 18 years ago, I was quite a fan of oncology trials. The treatment of childhood cancer seemed to me a great illustration of how incremental advances which seemed small in themselves could eventually achieve major improvements in survival. And so they have, but at a cost. In this study of 23 603 survivors of childhood cancer, there were 1026 new malignancies over a mean follow up of 20.5 years. The strongest association was with radiation dosage, which tended to fall between the 1970s and the 1990s. Just one more reminder that ionizing radiation is bad for children, and treatment regimens that reduce the need for it are likely to be a good thing.

Early onset type 2 diabetes is bad news

Here’s an observational study comparing 1746 patients who developed type 1 diabetes before the age of 20 with 272 who had type 2 diabetes, also with onset before 20. The prevalence of diabetic kidney disease, retinopathy, and peripheral neuropathy was significantly greater in patients with type 2 diabetes, even after adjustment for differences in hemoglobin A1c, body mass index, waist-height ratio, and mean arterial blood pressure. This is very worrying. One could quibble about the adjustments and the detail, but this survey provides more proof that with type 2 diabetes, age of onset is a crucial factor. Once it is established, this syndrome does major damage which we are still largely unable to control.

Antithrombotics and subdural haemorrhage

The Danish population registry shows that the incidence of subdural haemorrhage almost doubled between 2000 and 2015. By comparing 10,010 cases with 400,380 matched controls, the investigators in this study were able to calculate how much of this might be due to drugs which impair clotting. The odds ratio for people taking aspirin was 1.25, while for direct oral anticoagulants it was 1.73. Surprisingly, clopidogrel came in at 1.87. But by far the greatest increase in risk was associated with vitamin K antagonists, at 3.69. Beware the elderly patient taking warfarin who “goes off”, with or without a headache.

JAMA Intern Med  Feb 2017 Vol 177

REMIND me – what was I supposed to take?

Poor adherence to prescribed medicines is not just a problem of elderly people taking numerous different pills. The REMIND trial recruited 53 480 people aged between 18 and 64 who were taking no more than three types of medication a day but nevertheless showed “non-adherence”, meaning less than 80% of indicated use.  They were block-randomised to receive a pill-bottle strip with toggles, a digital timer cap, a standard pill bottle, or nothing. Never mind trying to work out the strip-and-toggle bit: none of these interventions made any difference.

Pioglitazone for NASH?

As the developed world gets fatter from eating nicer food, an increasing number of adults are classed as having non-alcoholic steatohepatitis. One way to avoid this diagnosis is to drink more alcohol than the definition permits. Another is to eat less nice food. Another is to forget about it. NASH does not alter the lifespan of those who have the label, unless it progresses to advanced liver fibrosis, whereupon it is likely to cause liver failure and death. So for those with fibrosis who wish to postpone death, an effective drug would be welcome, and it seems that pioglitazone may be a candidate. The conclusion of this meta-analysis of all trials of thiazolidinediones for NASH is that “pioglitazone improves advanced fibrosis in NASH, even in people without diabetes.” But if you look at the tables, you’ll see that this statement is based on histological evidence from 5 trials which randomized a total of 74 people with advanced fibrosis attributed to NASH. So it’s definitely not a green light for using pioglitazone in anything but a large randomised trial of people with known liver fibrosis.

The Lancet  4 Mar 2017 Vol 389

Early life deprivation

Remember those awful pictures of Romanian orphans from 25 years ago? A longitudinal study compares those who were adopted by English parents with UK controls who had not experienced early-life deprivation. Cognitive impairment in the group who spent more than 6 months in an institution remitted from markedly higher rates at ages 6 years and 11 years compared with UK controls, to normal rates at young adulthood. But for psychosocial adjustment, it was a very different story: “extended early deprivation was associated with long-term deleterious effects on wellbeing that seem insusceptible to years of nurturance and support in adoptive families.” Please could The Lancet take on a retired English schoolteacher to take a red pencil to this stuff? “Nurturance”? Deleterious, insusceptible. Pah. The most striking fact here is that the kids who had spent over 6 months in Romanian orphanages coped reasonably while they were with their foster parents, but from the age of 15 onwards showed increasing levels of emotional distress and educational and social failure.

Selling liraglutide for “prediabetes”

Between us, we pampered adults in the rich world can hardly avoid having NASH, pre-hypertension or pre-diabetes. No wonder we live so long. Overweight and obese adults who think they have pre-diabetes can inject themselves with liraglutide. What this will achieve in the long-term is anyone’s guess, except for shareholders in NovoNordisk, who know it will improve their profits. In this 3-year trial, half the participants dropped out. The ones who injected themselves daily with liraglutide took longer to cross the arbitrary line which defines type 2 diabetes, which is what you would expect, since the one thing we know about liraglutide is that it lowers blood sugar a bit.

Speech therapy for stroke aphasia

In this multicentre, parallel group, superiority, open-label, blinded-endpoint, randomised controlled trial, patients aged 70 years or younger with aphasia after stroke lasting for 6 months or more were recruited from 19 inpatient or outpatient rehabilitation centres in Germany.” If only the words “were recruited” had been left to the end, this would have been a great example of an academic German sentence. The participants, you will gather, were still without speech over six months after their stroke. The intervention was 3 weeks or more of speech and language therapy lasting more than 10 hours a week. This brought about some improvement, but the investigators conclude that future studies should examine the minimum treatment intensity required for meaningful treatment effects, and determine whether treatment effects cumulate over repeated intervention periods.

The BMJ  4 Mar 2017  Vol 356

Flu antivirals safe in pregnancy

One of the scariest things about new influenza epidemics is that they can cause death in fit young women during or just after pregnancy. I’m sceptical about the effectiveness of neuraminidase inhibitors for flu in the general population, but I can see an argument for using them prophylactically in gravid and postnatal women who cannot be protected by an effective vaccine during an epidemic. So it’s good to know that in an observational cohort study covering the populations of three Scandinavian countries, there is no signal for adverse neonatal outcomes or congenital malformations associated with exposure to neuraminidase inhibitors during embryo-fetal life.

Adiposity and cancer

Nature has designed us to hold on to excess fat in case we can’t find enough food. It never designed us to live sedentary lives amidst plenty, though that is what most humans do given the chance. People who get fat early in life certainly have a reduced life expectancy compared with those who don’t, but fortunately for me, this evens out or even reverses with age. I like it that this “umbrella review of the literature” reports that ” Although the association of adiposity with cancer risk has been extensively studied, associations for only 11 cancers were supported by strong evidence.” Only eleven: well, that’s all right then. The cancers in question are oesophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

Plant of the Week: Magnolias as metaphors

London is about a flowering month ahead of our garden in the sticks, so I wondered if we would see magnolias in flower when we went to join the NHS march on Saturday. In fact we saw two, one at the start and one at the finish.

The first magnolias are thought to have flowered about 90 million years ago, meaning that they lived alongside dinosaurs for over 20 million years. They may have relied on pollination by beetles, since bees were in short supply in the Cretaceous period. The magnolia formula for success was and remains simple and robust: quick growth, big leaves for photosynthesis and big tough flowers, usually white and heavily scented to attract night-flying beetles. They survived the Cretaceous extinctions in the Far East and the American continent, and became very popular when introduced into Europe during the eighteenth and nineteenth centuries.

We arrived far too early in Tavistock Square and spotted a magnolia which was just coming into flower. It was a small specimen of the common soulangeana hybrid: a mean, municipal choice for a well-favoured location which could easily have housed a resplendent tall tree like Magnolia campbelli or one of its many offspring. After some delay, we marched about two miles with a quarter of million people to reach Parliament Square, where we spotted another magnolia, this time in full flower. It was a shrubby little variety of M kobus with flimsy white strap flowers, called stellata. Another mean municipal choice, when the true parent tree could have grown to 10 metres and have been covered by scented white flowers, perfectly able to cope with the surrounding traffic.

We stayed to listen to Jeremy Corbyn’s speech, which listed all the admirable things which were needed to sustain the NHS, if only we had an opposition party capable of being elected.

Spiritual London is a strange place, and half the time I had the feeling of being inside someone else’s dystopic brain. The handsome Georgian black brick facades of Bloomsbury were interspersed with glimpses of massive white London University power statements from the 1930s. Curiously, William Beveridge was as much responsible for these as for the National Health Service. Among the crowded shopping streets, late Victorian chapels of various denominations survive, all built of greenish brick in various versions of Ruskin Italian Gothic. Whitehall declared an eternal imperial solidity which hardly lasted the period of its construction. The Houses of Parliament stood beautifully against a cloud-flecked blue sky, as we sat incongruously by the foot of a massive bronze statue of General Smuts. I was carrying a banner made by the Socialist Party, something I didn’t know existed.

Many of the banners proclaimed a welcome to migrants, without whom the NHS could not function. Lloyd George, leaning forward with a strange flapping coat of heavy bronze, looked on. Bevan was quoted on a thousand placards. After Corbyn, the huge crowd dispersed and we left behind the small tattered magnolia in Parliament Square. With different choices and the right encouragement, perhaps it could have grown into the tree of heaven, whose leaves are for the healing of nations.