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Sunday, July 3, 2022

Paleocene–Eocene Thermal Maximum

Climate change during the last 65 million years as expressed by the oxygen isotope composition of benthic foraminifera. The Paleocene-Eocene Thermal Maximum (PETM) is characterized by a brief but prominent negative excursion, attributed to rapid warming. Note that the excursion is understated in this graph due to the smoothing of data.

The Paleocene–Eocene Thermal Maximum (PETM), alternatively "Eocene thermal maximum 1" (ETM1), and formerly known as the "Initial Eocene" or "Late Paleocene Thermal Maximum", was a time period with a more than 5–8 °C global average temperature rise across the event. This climate event occurred at the time boundary of the Paleocene and Eocene geological epochs. The exact age and duration of the event is uncertain but it is estimated to have occurred around 55.5 million years ago.

The associated period of massive carbon release into the atmosphere has been estimated to have lasted from 20,000 to 50,000 years. The entire warm period lasted for about 200,000 years. Global temperatures increased by 5–8 °C.

The onset of the Paleocene–Eocene Thermal Maximum has been linked to volcanism and uplift associated with the North Atlantic Igneous Province, causing extreme changes in Earth's carbon cycle and a significant temperature rise. The period is marked by a prominent negative excursion in carbon stable isotope (δ13C) records from around the globe; more specifically, there was a large decrease in 13C/12C ratio of marine and terrestrial carbonates and organic carbon. Paired δ13C, δ11B, and δ18O data suggest that ~12000 Gt of carbon (at least 44000 Gt CO2e) were released over 50,000 years, averaging 0.24 Gt per year.

Stratigraphic sections of rock from this period reveal numerous other changes. Fossil records for many organisms show major turnovers. For example, in the marine realm, a mass extinction of benthic foraminifera, a global expansion of subtropical dinoflagellates, and an appearance of excursion, planktic foraminifera and calcareous nanofossils all occurred during the beginning stages of PETM. On land, modern mammal orders (including primates) suddenly appear in Europe and in North America. Sediment deposition changed significantly at many outcrops and in many drill cores spanning this time interval.

Since at least 1997, the Paleocene–Eocene Thermal Maximum has been investigated in geoscience as an analog to understand the effects of global warming and of massive carbon inputs to the ocean and atmosphere, including ocean acidification. Humans today emit about 10 Gt of carbon (about 37 Gt CO2e) per year, and will have released a comparable amount in about 1,000 years at that rate. A main difference is that during the Paleocene–Eocene Thermal Maximum, the planet was ice-free, as the Drake Passage had not yet opened and the Central American Seaway had not yet closed. Although the PETM is now commonly held to be a "case study" for global warming and massive carbon emission, the cause, details, and overall significance of the event remain uncertain.

Setting

The configuration of oceans and continents was somewhat different during the early Paleogene relative to the present day. The Panama Isthmus did not yet connect North America and South America, and this allowed direct low-latitude circulation between the Pacific and Atlantic Oceans. The Drake Passage, which now separates South America and Antarctica, was closed, and this perhaps prevented thermal isolation of Antarctica. The Arctic was also more restricted. Although various proxies for past atmospheric CO2 levels in the Eocene do not agree in absolute terms, all suggest that levels then were much higher than at present. In any case, there were no significant ice sheets during this time.

Earth surface temperatures increased by about 6 °C from the late Paleocene through the early Eocene, culminating in the "Early Eocene Climatic Optimum" (EECO). Superimposed on this long-term, gradual warming were at least two (and probably more) "hyperthermals". These can be defined as geologically brief (<200,000 year) events characterized by rapid global warming, major changes in the environment, and massive carbon addition. Of these, the PETM was the most extreme and perhaps the first (at least within the Cenozoic). Another hyperthermal clearly occurred at approximately 53.7 Ma, and is now called ETM-2 (also referred to as H-1, or the Elmo event). However, additional hyperthermals probably occurred at about 53.6 Ma (H-2), 53.3 (I-1), 53.2 (I-2) and 52.8 Ma (informally called K, X or ETM-3). The number, nomenclature, absolute ages, and relative global impact of the Eocene hyperthermals are the source of considerable current research. Whether they only occurred during the long-term warming, and whether they are causally related to apparently similar events in older intervals of the geological record (e.g. the Toarcian turnover of the Jurassic) are open issues.

Acidification of deep waters, and the later spreading from the North Atlantic can explain spatial variations in carbonate dissolution. Model simulations show acidic water accumulation in the deep North Atlantic at the onset of the event.

Evidence for global warming

A stacked record of temperatures and ice volume in the deep ocean through the Mesozoic and Cenozoic periods.
LPTM— Paleocene-Eocene Thermal Maximum
OAEs— Oceanic Anoxic Events
MME— Mid-Maastrichtian Event

At the start of the PETM, average global temperatures increased by approximately 6 °C (11 °F) within about 20,000 years. This warming was superimposed on "long-term" early Paleogene warming, and is based on several lines of evidence. There is a prominent (>1) negative excursion in the δ18O of foraminifera shells, both those made in surface and deep ocean water. Because there was a paucity of continental ice in the early Paleogene, the shift in δ18O very probably signifies a rise in ocean temperature. The temperature rise is also supported by analyses of fossil assemblages, the Mg/Ca ratios of foraminifera, and the ratios of certain organic compounds, such as TEX86.

Precise limits on the global temperature rise during the PETM and whether this varied significantly with latitude remain open issues. Oxygen isotope and Mg/Ca of carbonate shells precipitated in surface waters of the ocean are commonly used measurements for reconstructing past temperature; however, both paleotemperature proxies can be compromised at low latitude locations, because re-crystallization of carbonate on the seafloor renders lower values than when formed. On the other hand, these and other temperature proxies (e.g., TEX86) are impacted at high latitudes because of seasonality; that is, the “temperature recorder” is biased toward summer, and therefore higher values, when the production of carbonate and organic carbon occurred.

Certainly, the central Arctic Ocean was ice-free before, during, and after the PETM. This can be ascertained from the composition of sediment cores recovered during the Arctic Coring Expedition (ACEX) at 87°N on Lomonosov Ridge. Moreover, temperatures increased during the PETM, as indicated by the brief presence of subtropical dinoflagellates, and a marked increase in TEX86. The latter record is intriguing, though, because it suggests a 6 °C (11 °F) rise from ~17 °C (63 °F) before the PETM to ~23 °C (73 °F) during the PETM. Assuming the TEX86 record reflects summer temperatures, it still implies much warmer temperatures on the North Pole compared to the present day, but no significant latitudinal amplification relative to surrounding time.

The above considerations are important because, in many global warming simulations, high latitude temperatures increase much more at the poles through an ice–albedo feedback. It may be the case, however, that during the PETM, this feedback was largely absent because of limited polar ice, so temperatures on the Equator and at the poles increased similarly.

Evidence for carbon addition

Clear evidence for massive addition of 13C-depleted carbon at the onset of the PETM comes from two observations. First, a prominent negative excursion in the carbon isotope composition (δ13C) of carbon-bearing phases characterizes the PETM in numerous (>130) widespread locations from a range of environments. Second, carbonate dissolution marks the PETM in sections from the deep sea.

The total mass of carbon injected to the ocean and atmosphere during the PETM remains the source of debate. In theory, it can be estimated from the magnitude of the negative carbon isotope excursion (CIE), the amount of carbonate dissolution on the seafloor, or ideally both. However, the shift in the δ13C across the PETM depends on the location and the carbon-bearing phase analyzed. In some records of bulk carbonate, it is about 2‰ (per mil); in some records of terrestrial carbonate or organic matter it exceeds 6‰. Carbonate dissolution also varies throughout different ocean basins. It was extreme in parts of the north and central Atlantic Ocean, but far less pronounced in the Pacific Ocean. With available information, estimates of the carbon addition range from about 2,000 to 7,000 gigatons.

Comparison with today's climate change

Model simulations of peak carbon addition to the ocean–atmosphere system during the PETM give a probable range of 0.3–1.7 petagrams of carbon per year (Pg C/yr), which is much slower than the currently observed rate of carbon emissions. It has been suggested that today's methane emission regime from the ocean floor is potentially similar to that during the PETM. (One petagram of carbon = 1 gigaton of carbon, GtC; the current rate of carbon injection into the atmosphere is over 10 GtC/yr, much larger than the carbon injection rate that occurred during the PETM.)

Professor of Earth and planetary sciences James Zachos notes that IPCC projections for 2300 in the 'business-as-usual' scenario could "potentially bring global temperature to a level the planet has not seen in 50 million years" – during the early Eocene. Some have described the PETM as arguably the best ancient analog of modern climate change. Scientists have investigated effects of climate change on chemistry of the oceans by exploring oceanic changes during the PETM.

A study found that the PETM shows that substantial climate-shifting tipping points in the Earth system exist, which "can trigger release of additional carbon reservoirs and drive Earth's climate into a hotter state".

Timing of carbon addition and warming

The timing of the PETM δ13C excursion is of considerable interest. This is because the total duration of the CIE, from the rapid drop in δ13C through the near recovery to initial conditions, relates to key parameters of our global carbon cycle, and because the onset provides insight to the source of 13C-depleted CO2.

The total duration of the CIE can be estimated in several ways. The iconic sediment interval for examining and dating the PETM is a core recovered in 1987 by the Ocean Drilling Program at Hole 690B at Maud Rise in the South Atlantic Ocean. At this location, the PETM CIE, from start to end, spans about 2 m. Long-term age constraints, through biostratigraphy and magnetostratigraphy, suggest an average Paleogene sedimentation rate of about 1.23 cm/1,000yrs. Assuming a constant sedimentation rate, the entire event, from onset though termination, was therefore estimated at 200,000 years. Subsequently, it was noted that the CIE spanned 10 or 11 subtle cycles in various sediment properties, such as Fe content. Assuming these cycles represent precession, a similar but slightly longer age was calculated by Rohl et al. 2000. A ~200,000 year duration for the CIE is estimated from models of global carbon cycling. If a massive amount of 13C-depleted CO2 is rapidly injected into the modern ocean or atmosphere and projected into the future, a ~200,000 year CIE results because of slow flushing through quasi steady-state inputs (weathering and volcanism) and outputs (carbonate and organic) of carbon.

The above approach can be performed at many sections containing the PETM. This has led to an intriguing result. At some locations (mostly deep-marine), sedimentation rates must have decreased across the PETM, presumably because of carbonate dissolution on the seafloor; at other locations (mostly shallow-marine), sedimentation rates must have increased across the PETM, presumably because of enhanced delivery of riverine material during the event.

Age constraints at several deep-sea sites have been independently examined using 3He contents, assuming the flux of this cosmogenic nuclide is roughly constant over short time periods. This approach also suggests a rapid onset for the PETM CIE (<20,000 years). However, the 3He records support a faster recovery to near initial conditions (<100,000 years) than predicted by flushing via weathering inputs and carbonate and organic outputs.

There is other evidence to suggest that warming predated the δ13C excursion by some 3,000 years.

Effects

Weather

Azolla floating ferns, fossils of this genus indicate subtropical weather at the North Pole

The climate would also have become much wetter, with the increase in evaporation rates peaking in the tropics. Deuterium isotopes reveal that much more of this moisture was transported polewards than normal. Warm weather would have predominated as far north as the Polar basin. Finds of fossils of Azolla floating ferns in polar regions indicate subtropic temperatures at the poles. The Messel pit biota, dated to the middle of the thermal maximum, indicate a tropical rainforest environment in South Germany. Unlike modern rainforests, its latitude would have made it seasonal combined with equatorial temperatures, a weather system and corresponding environment unmatched anywhere on Earth today.

Ocean

The amount of freshwater in the Arctic Ocean increased, in part due to northern hemisphere rainfall patterns, fueled by poleward storm track migrations under global warming conditions.

Anoxia

In parts of the oceans, especially the north Atlantic Ocean, bioturbation was absent. This may be due to bottom-water anoxia, or by changing ocean circulation patterns changing the temperatures of the bottom water. However, many ocean basins remained bioturbated through the PETM.

Sea level

Along with the global lack of ice, the sea level would have risen due to thermal expansion. Evidence for this can be found in the shifting palynomorph assemblages of the Arctic Ocean, which reflect a relative decrease in terrestrial organic material compared to marine organic matter.

Currents

At the start of the PETM, the ocean circulation patterns changed radically in the course of under 5,000 years. Global-scale current directions reversed due to a shift in overturning from the southern hemisphere to northern hemisphere overturning. This "backwards" flow persisted for 40,000 years. Such a change would transport warm water to the deep oceans, enhancing further warming.

Lysocline

The lysocline marks the depth at which carbonate starts to dissolve (above the lysocline, carbonate is oversaturated): today, this is at about 4 km, comparable to the median depth of the oceans. This depth depends on (among other things) temperature and the amount of CO2 dissolved in the ocean. Adding CO2 initially raises the lysocline, resulting in the dissolution of deep water carbonates. This deep-water acidification can be observed in ocean cores, which show (where bioturbation has not destroyed the signal) an abrupt change from grey carbonate ooze to red clays (followed by a gradual grading back to grey). It is far more pronounced in north Atlantic cores than elsewhere, suggesting that acidification was more concentrated here, related to a greater rise in the level of the lysocline. In parts of the southeast Atlantic, the lysocline rose by 2 km in just a few thousand years.

Life

Stoichiometric magnetite (Fe
3
O
4
) particles were obtained from PETM-age marine sediments. The study from 2008 found elongate prism and spearhead crystal morphologies, considered unlike any magnetite crystals previously reported, and are potentially of biogenic origin. These biogenic magnetite crystals show unique gigantism, and probably are of aquatic origin. The study suggests that development of thick suboxic zones with high iron bioavailability, the result of dramatic changes in weathering and sedimentation rates, drove diversification of magnetite-forming organisms, likely including eukaryotes. Biogenic magnetites in animals have a crucial role in geomagnetic field navigation.

Ocean

The PETM is accompanied by a mass extinction of 35–50% of benthic foraminifera (especially in deeper waters) over the course of ~1,000 years – the group suffering more than during the dinosaur-slaying K-T extinction. Contrarily, planktonic foraminifera diversified, and dinoflagellates bloomed. Success was also enjoyed by the mammals, who radiated extensively around this time.

The deep-sea extinctions are difficult to explain, because many species of benthic foraminifera in the deep-sea are cosmopolitan, and can find refugia against local extinction. General hypotheses such as a temperature-related reduction in oxygen availability, or increased corrosion due to carbonate undersaturated deep waters, are insufficient as explanations. Acidification may also have played a role in the extinction of the calcifying foraminifera, and the higher temperatures would have increased metabolic rates, thus demanding a higher food supply. Such a higher food supply might not have materialized because warming and increased ocean stratification might have led to declining productivity and/or increased remineralization of organic matter in the water column, before it reached the benthic foraminifera on the sea floor. The only factor global in extent was an increase in temperature. Regional extinctions in the North Atlantic can be attributed to increased deep-sea anoxia, which could be due to the slowdown of overturning ocean currents, or the release and rapid oxidation of large amounts of methane. Oxygen minimum zones in the oceans may have expanded.

In shallower waters, it's undeniable that increased CO2 levels result in a decreased oceanic pH, which has a profound negative effect on corals. Experiments suggest it is also very harmful to calcifying plankton. However, the strong acids used to simulate the natural increase in acidity which would result from elevated CO2 concentrations may have given misleading results, and the most recent evidence is that coccolithophores (E. huxleyi at least) become more, not less, calcified and abundant in acidic waters. No change in the distribution of calcareous nanoplankton such as the coccolithophores can be attributed to acidification during the PETM. Acidification did lead to an abundance of heavily calcified algae and weakly calcified forams.

A study published in May 2021 concluded that fish thrived in at least some tropical areas during the PETM, based on discovered fish fossils including Mene maculata at Ras Gharib, Egypt.

Land

Humid conditions caused migration of modern Asian mammals northward, dependent on the climatic belts. Uncertainty remains for the timing and tempo of migration.

The increase in mammalian abundance is intriguing. Increased CO2 levels may have promoted dwarfing – which may have encouraged speciation. Many major mammalian orders – including the Artiodactyla, horses, and primates – appeared and spread around the globe 13,000 to 22,000 years after the initiation of the PETM.

Temperature

Proxy data from one of the studied sites show rapid +8 °C temperature rise, in accordance with existing regional records of marine and terrestrial environments. Notable is the absence of documented greater warming in polar regions. This implies a non-existing ice-albedo feedback, suggesting no sea or land ice was present in the late Paleocene.

Terrestrial

During the PETM, sediments are enriched with kaolinite from a detrital source due to denudation (initial processes such as volcanoes, earthquakes, and plate tectonics). This suggests increased precipitation, and enhanced erosion of older kaolinite-rich soils and sediments. Increased weathering from the enhanced runoff formed thick paleosoil enriched with carbonate nodules (Microcodium like), and this suggests a semi-arid climate.

Possible causes

Discriminating between different possible causes of the PETM is difficult. Temperatures were rising globally at a steady pace, and a mechanism must be invoked to produce an instantaneous spike which may have been accentuated or catalyzed by positive feedback (or activation of "tipping or points"). The biggest aid in disentangling these factors comes from a consideration of the carbon isotope mass balance. We know the entire exogenic carbon cycle (i.e. the carbon contained within the oceans and atmosphere, which can change on short timescales) underwent a −0.2 % to −0.3 % perturbation in δ13C, and by considering the isotopic signatures of other carbon reserves, can consider what mass of the reserve would be necessary to produce this effect. The assumption underpinning this approach is that the mass of exogenic carbon was the same in the Paleogene as it is today – something which is very difficult to confirm.

Eruption of large kimberlite field

Although the cause of the initial warming has been attributed to a massive injection of carbon (CO2 and/or CH4) into the atmosphere, the source of the carbon has yet to be found. The emplacement of a large cluster of kimberlite pipes at ~56 Ma in the Lac de Gras region of northern Canada may have provided the carbon that triggered early warming in the form of exsolved magmatic CO2. Calculations indicate that the estimated 900–1,100 Pg of carbon required for the initial approximately 3 °C of ocean water warming associated with the Paleocene-Eocene thermal maximum could have been released during the emplacement of a large kimberlite cluster. The transfer of warm surface ocean water to intermediate depths led to thermal dissociation of seafloor methane hydrates, providing the isotopically depleted carbon that produced the carbon isotopic excursion. The coeval ages of two other kimberlite clusters in the Lac de Gras field and two other early Cenozoic hyperthermals indicate that CO2 degassing during kimberlite emplacement is a plausible source of the CO2 responsible for these sudden global warming events.

Volcanic activity

Satellite photo of Ardnamurchan – with clearly visible circular shape, which is the 'plumbings of an ancient volcano'

To balance the mass of carbon and produce the observed δ13C value, at least 1,500 gigatons of carbon would have to degas from the mantle via volcanoes over the course of the two, 1,000 year, steps. To put this in perspective, this is about 200 times the background rate of degassing for the rest of the Paleocene. There is no indication that such a burst of volcanic activity has occurred at any point in Earth's history. However, substantial volcanism had been active in East Greenland for around the preceding million years or so, but this struggles to explain the rapidity of the PETM. Even if the bulk of the 1,500 gigatons of carbon was released in a single pulse, further feedbacks would be necessary to produce the observed isotopic excursion.

On the other hand, there are suggestions that surges of activity occurred in the later stages of the volcanism and associated continental rifting. Intrusions of hot magma into carbon-rich sediments may have triggered the degassing of isotopically light methane in sufficient volumes to cause global warming and the observed isotope anomaly. This hypothesis is documented by the presence of extensive intrusive sill complexes and thousands of kilometer-sized hydrothermal vent complexes in sedimentary basins on the mid-Norwegian margin and west of Shetland. Volcanic eruptions of a large magnitude can impact global climate, reducing the amount of solar radiation reaching the Earth's surface, lowering temperatures in the troposphere, and changing atmospheric circulation patterns. Large-scale volcanic activity may last only a few days, but the massive outpouring of gases and ash can influence climate patterns for years. Sulfuric gases convert to sulfate aerosols, sub-micron droplets containing about 75 percent sulfuric acid. Following eruptions, these aerosol particles can linger as long as three to four years in the stratosphere. Further phases of volcanic activity could have triggered the release of more methane, and caused other early Eocene warm events such as the ETM2. It has also been suggested that volcanic activity around the Caribbean may have disrupted the circulation of oceanic currents, amplifying the magnitude of climate change.

A 2017 study noted strong evidence of a volcanic carbon source (greater than 10,000 petagrams of carbon), associated with the North Atlantic Igneous Province. A 2021 study found the PETM was directly preceded by volcanism.

Comet impact

A briefly popular theory held that a 12C-rich comet struck the earth and initiated the warming event. A cometary impact coincident with the P/E boundary can also help explain some enigmatic features associated with this event, such as the iridium anomaly at Zumaia, the abrupt appearance of kaolinitic clays with abundant magnetic nanoparticles on the coastal shelf of New Jersey, and especially the nearly simultaneous onset of the carbon isotope excursion and the thermal maximum. Indeed, a key feature and testable prediction of a comet impact is that it should produce virtually instantaneous environmental effects in the atmosphere and surface ocean with later repercussions in the deeper ocean. Even allowing for feedback processes, this would require at least 100 gigatons of extraterrestrial carbon. Such a catastrophic impact should have left its mark on the globe. However, the evidence put forward does not stand up to scrutiny. An unusual 9-meter-thick clay layer supposedly formed soon after the impact, containing unusual amounts of magnetite, but it formed too slowly for these magnetic particles to have been a result of the comet's impact. and it turns out they were created by bacteria. However, recent analyses have shown that isolated particles of non-biogenic origin make up the majority of the magnetic particles in the thick clay unit.

A 2016 report in Science describes the discovery of impact ejecta from three marine P-E boundary sections from the Atlantic margin of the eastern U.S., indicating that an extraterrestrial impact occurred during the carbon isotope excursion at the P-E boundary. The silicate glass spherules found were identified as microtektites and microkrystites.

Burning of peat

The combustion of prodigious quantities of peat was once postulated, because there was probably a greater mass of carbon stored as living terrestrial biomass during the Paleocene than there is today since plants in fact grew more vigorously during the period of the PETM. This theory was refuted, because in order to produce the δ13C excursion observed, over 90 percent of the Earth's biomass would have to have been combusted. However, the Paleocene is also recognized as a time of significant peat accumulation worldwide. A comprehensive search failed to find evidence for the combustion of fossil organic matter, in the form of soot or similar particulate carbon.

Orbital forcing

The presence of later (smaller) warming events of a global scale, such as the Elmo horizon (aka ETM2), has led to the hypothesis that the events repeat on a regular basis, driven by maxima in the 400,000 and 100,000 year eccentricity cycles in the Earth's orbit. The current warming period is expected to last another 50,000 years due to a minimum in the eccentricity of the Earth's orbit. Orbital increase in insolation (and thus temperature) would force the system over a threshold and unleash positive feedbacks.

Methane release

None of the above causes are alone sufficient to cause the carbon isotope excursion or warming observed at the PETM. The most obvious feedback mechanism that could amplify the initial perturbation is that of methane clathrates. Under certain temperature and pressure conditions, methane – which is being produced continually by decomposing microbes in sea bottom sediments – is stable in a complex with water, which forms ice-like cages trapping the methane in solid form. As temperature rises, the pressure required to keep this clathrate configuration stable increases, so shallow clathrates dissociate, releasing methane gas to make its way into the atmosphere. Since biogenic clathrates have a δ13C signature of −60 ‰ (inorganic clathrates are the still rather large −40 ‰), relatively small masses can produce large δ13C excursions. Further, methane is a potent greenhouse gas as it is released into the atmosphere, so it causes warming, and as the ocean transports this warmth to the bottom sediments, it destabilizes more clathrates. It would take around 2,300 years for an increased temperature to diffuse warmth into the sea bed to a depth sufficient to cause a release of clathrates, although the exact time-frame is highly dependent on a number of poorly constrained assumptions. Ocean warming due to flooding and pressure changes due to a sea-level drop may have caused clathrates to become unstable and release methane. This can take place over as short of a period as a few thousand years. The reverse process, that of fixing methane in clathrates, occurs over a larger scale of tens of thousands of years.

In order for the clathrate hypothesis to work, the oceans must show signs of having been warmer slightly before the carbon isotope excursion, because it would take some time for the methane to become mixed into the system and δ13C-reduced carbon to be returned to the deep ocean sedimentary record. Until recently, the evidence suggested that the two peaks were in fact simultaneous, weakening the support for the methane theory. But recent (2002) work has managed to detect a short gap between the initial warming and the δ13C excursion. Chemical markers of surface temperature (TEX86) also indicate that warming occurred around 3,000 years before the carbon isotope excursion, but this does not seem to hold true for all cores. Notably, deeper (non-surface) waters do not appear to display evidence of this time gap. Moreover, the small apparent change in TEX86 that precede the δ13C anomaly can easily (and more plausibly) be ascribed to local variability (especially on the Atlantic coastal plain, e.g. Sluijs, et al., 2007) as the TEX86 paleo-thermometer is prone to significant biological effects. The δ18O of benthic or planktonic forams does not show any pre-warming in any of these localities, and in an ice-free world, it is generally a much more reliable indicator of past ocean temperatures.

Analysis of these records reveals another interesting fact: planktonic (floating) forams record the shift to lighter isotope values earlier than benthic (bottom dwelling) forams. The lighter (lower δ13C) methanogenic carbon can only be incorporated into the forams' shells after it has been oxidised. A gradual release of the gas would allow it to be oxidised in the deep ocean, which would make benthic forams show lighter values earlier. The fact that the planktonic forams are the first to show the signal suggests that the methane was released so rapidly that its oxidation used up all the oxygen at depth in the water column, allowing some methane to reach the atmosphere unoxidised, where atmospheric oxygen would react with it. This observation also allows us to constrain the duration of methane release to under around 10,000 years.

However, there are several major problems with the methane hydrate dissociation hypothesis. The most parsimonious interpretation for surface-water forams to show the δ13C excursion before their benthic counterparts (as in the Thomas et al. paper) is that the perturbation occurred from the top down, and not the bottom up. If the anomalous δ13C (in whatever form: CH4 or CO2) entered the atmospheric carbon reservoir first, and then diffused into the surface ocean waters, which mix with the deeper ocean waters over much longer time-scales, we would expect to observe the planktonics shifting toward lighter values before the benthics. Moreover, careful examination of the Thomas et al. data set shows that there is not a single intermediate planktonic foram value, implying that the perturbation and attendant δ13C anomaly happened over the lifespan of a single foram – much too fast for the nominal 10,000-year release needed for the methane hypothesis to work.

There is a debate about whether there was a large enough amount of methane hydrate to be a major carbon source; a recent paper proposed that was the case. The present-day global methane hydrate reserve is poorly constrained, but is mostly considered to be between 2,000 and 10,000 Gt. However, because the global ocean bottom temperatures were ~6 °C higher than today, which implies a much smaller volume of sediment hosting gas hydrate than today, the global amount of hydrate before the PETM has been thought to be much less than present-day estimates. in a 2006 study, scientists regarded the source of carbon for the PETM to be a mystery. A 2011 study, using numerical simulations suggests that enhanced organic carbon sedimentation and methanogenesis could have compensated for the smaller volume of hydrate stability.

A 2016 study based on reconstructions of atmospheric CO2 content during the PETM's carbon isotope excursions (CIE), using triple oxygen isotope analysis, suggests a massive release of seabed methane into the atmosphere as the driver of climatic changes. The authors also note:

A massive release of methane clathrates by thermal dissociation has been the most convincing hypothesis to explain the CIE since it was first identified.

Ocean circulation

The large scale patterns of ocean circulation are important when considering how heat was transported through the oceans. Our understanding of these patterns is still in a preliminary stage. Models show that there are possible mechanisms to quickly transport heat to the shallow, clathrate-containing ocean shelves, given the right bathymetric profile, but the models cannot yet match the distribution of data we observe. "Warming accompanying a south-to-north switch in deepwater formation would produce sufficient warming to destabilize seafloor gas hydrates over most of the world ocean to a water depth of at least 1900 m." This destabilization could have resulted in the release of more than 2000 gigatons of methane gas from the clathrate zone of the ocean floor.

Arctic freshwater input into the North Pacific could serve as a catalyst for methane hydrate destabilization, an event suggested as a precursor to the onset of the PETM.

Recovery

Climate proxies, such as ocean sediments (depositional rates) indicate a duration of ∼83 ka, with ∼33 ka in the early rapid phase and ∼50 ka in a subsequent gradual phase.

The most likely method of recovery involves an increase in biological productivity, transporting carbon to the deep ocean. This would be assisted by higher global temperatures and CO2 levels, as well as an increased nutrient supply (which would result from higher continental weathering due to higher temperatures and rainfall; volcanoes may have provided further nutrients). Evidence for higher biological productivity comes in the form of bio-concentrated barium. However, this proxy may instead reflect the addition of barium dissolved in methane. Diversifications suggest that productivity increased in near-shore environments, which would have been warm and fertilized by run-off, outweighing the reduction in productivity in the deep oceans.

Vitamin deficiency

From Wikipedia, the free encyclopedia
 
Vitamin deficiency
Other namesAvitaminosis, hypovitaminosis
SpecialtyEndocrinology

Vitamin deficiency is the condition of a long-term lack of a vitamin. When caused by not enough vitamin intake it is classified as a primary deficiency, whereas when due to an underlying disorder such as malabsorption it is called a secondary deficiency. An underlying disorder may be metabolic – as in a genetic defect for converting tryptophan to niacin – or from lifestyle choices that increase vitamin needs, such as smoking or drinking alcohol. Government guidelines on vitamin deficiencies advise certain intakes for healthy people, with specific values for women, men, babies, the elderly, and during pregnancy or breastfeeding. Many countries have mandated vitamin food fortification programs to prevent commonly occurring vitamin deficiencies.

Conversely, hypervitaminosis refers to symptoms caused by vitamin intakes in excess of needs, especially for fat-soluble vitamins that can accumulate in body tissues.

The history of the discovery of vitamin deficiencies progressed over centuries from observations that certain conditions – for example, scurvy – could be prevented or treated with certain foods having high content of a necessary vitamin, to the identification and description of specific molecules essential for life and health. During the 20th century, several scientists were awarded the Nobel Prize in Physiology or Medicine or the Nobel Prize in Chemistry for their roles in the discovery of vitamins.

Defining deficiency

A number of regions have published guidelines defining vitamin deficiencies and advising specific intakes for healthy people, with different recommendations for women, men, infants, the elderly, and during pregnancy and breast feeding including Japan, the European Union, the United States, and Canada. These documents have been updated as research is published. In the US, Recommended Dietary Allowances (RDAs) were first set in 1941 by the Food and Nutrition Board of the National Academy of Sciences. There were periodic updates, culminating in the Dietary Reference Intakes. Updated in 2016, the US Food and Drug Administration published a set of tables that define Estimated Average Requirements (EARs) and (RDAs). RDAs are higher to cover people with higher than average needs. Together, these are part of Dietary Reference Intakes. For a few vitamins, there is not sufficient information to set EARs and RDAs. For these, an Adequate Intake is shown, based on an assumption that what healthy people consume is sufficient. Countries do not always agree on the amounts of vitamins needed to safeguard against deficiency. For example, for vitamin C, the RDAs for women for Japan, the European Union (called Population Reference Intakes) and the US are 100, 95 and 75 mg/day, respectively. India sets its recommendation at 40 mg/day.

Individual vitamin deficiencies

Water-soluble vitamins

Vitamin Symptoms & Diagnosis Information
Thiamine (Vitamine B1) deficiency Weight loss, emotional disturbances, impaired sensory perception, weakness and pain in the limbs, and periods of irregular heart beat. Deficiency is assessed by red blood cell status and urinary output. Especially common in countries that do not require fortification of wheat and maize flour and rice to replace the naturally occurring thiamine content lost to milling, bleaching and other processing. Severe deficiency causes beriberi, which became prevalent in Asia as more people adopted a diet primarily of white rice. Wernicke encephalopathy and Korsakoff syndrome are forms of beriberi. Alcoholism can also cause vitamin deficiency.Long-term deficiencies can be life-threatening.
Riboflavin (Vitamine B2) deficiency Deficiency causes painful red tongue with sore throat, chapped and cracked lips, and inflammation at the corners of the mouth (angular cheilitis). Eyes can be itchy, watery, bloodshot and sensitive to light. Riboflavin deficiency also causes anemia with red blood cells that are normal in size and hemoglobin content, but reduced in number. This is distinct from anemia caused by deficiency of folic acid or vitamin B12. Especially common in countries that do not require fortification of wheat and maize flour and rice to replace the naturally occurring riboflavin lost during processing.
Niacin (Vitamine B3) deficiency Deficiency causes pellagra, a reversible nutritional wasting disease characterized by four classic symptoms often referred to as the four Ds: diarrhea, dermatitis, dementia, and death. The dermatitis occurs on areas of skin exposed to sunlight, such as backs of hands and neck. Niacin deficiency is a consequence of a diet low in both niacin and the amino acid tryptophan, a precursor for the vitamin. Low plasma tryptophan is a non-specific indicator, meaning it can have other causes. The signs and symptoms of niacin deficiency start to revert within days of oral supplementation with large amounts of the vitamin. Chronic alcoholism is a contributing risk factor.
Pantothenic acid (Vitamine B5) deficiency Irritability, fatigue, and apathy. Extremely rare.
Vitamin B6 deficiency microcytic anemia, electroencephalographic abnormalities, dermatitis, seborrhoeic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, and intertrigo. Neurologic symptoms of depression, somnolence, confusion, and neuropathy (due to impaired sphingosine synthesis) and microcytic anemia Uncommon, although it may be observed in certain conditions, such as end-stage kidney diseases or malabsorption syndromes, such as celiac disease, Crohn disease or ulcerative colitis.
Biotin (Vitamin B7) deficiency Rashes including red, patchy ones near the mouth and fine, brittle hair. Hallucinations, Lethargy, Mild depression, which may progress to profound fatigue and, eventually, to somnolence, Generalized muscular pains (myalgia) and Paresthesias. Decreased urinary excretion of biotin and increased urinary excretion of 3-hydroxyisovaleric acid are better indicators of biotin deficiency than concentration in the blood. Rare, although biotin status can be compromised in alcoholics and during pregnancy and breastfeeding.Deficiency affects hair growth and skin health.
Folate (Vitamin B9) deficiency Loss of appetite and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders. In adults, anemia (macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency. Common, and associated with numerous health problems, but primarily with neural tube defects (NTDs) in infants when the mother's plasma concentrations were low during the first third of pregnancies. Government-mandated fortification of foods with folic acid has reduced the incidence of NTDs by 25% to 50% in more than 60 countries using such fortification. Deficiency can also result from rare genetic factors, such as mutations in the MTHFR gene that lead to compromised folate metabolism. Cerebral folate deficiency is a rare condition in which concentrations of folate are low in the brain despite being normal in the blood.
Vitamin B12 deficiency Anemia (reduction of red blood cells), and the presence of limb neuropathy and digestive disorders. A mild deficiency may not cause any discernible symptoms, but at levels only lower than normal, a range of symptoms such as feeling tired and weak, feeling like passing out, headaches, dizziness, breathlessness (rapid), a sore red tongue (glossitis), low-grade fevers, shakiness and feeling permanently cold, rapid heartbeat, cold hands and feet, easy bruising and bleeding, pale skin, low blood pressure, nausea, stomach upset (dyspepsia), loss of appetite, weight loss, heartburn, constipation, diarrhea, severe joint pain, paresthesia in the hands and feet, and tinnitus, may be experienced. A wide range of associated symptoms may include angular cheilitis, mouth ulcers, bleeding gums, hair loss and thinning, premature greying, a look of exhaustion and dark circles around the eyes, as well as brittle nails. Lead to pernicious anemia, megaloblastic anemia, subacute combined degeneration of spinal cord, and methylmalonic acidemia, among other conditions. Supplementation with folate can mask vitamin B12 deficiency. Consuming a vegan diet increases the risk, since Vitamin B12 is only found in food and drinks made from animal products, including eggs and dairy products.
Vitamin C deficiency Deficiency leads to weakness, weight loss and general aches and pains. Longer-term depletion affects connective tissues, severe gum disease, and bleeding from the skin. Rare, consequently, no countries fortify foods as a means of preventing this deficiency. The historic importance of vitamin C deficiency relates to occurrence on long sea-going voyages, when the ship food supplies had no good source of the vitamin. Deficiency results in scurvy when plasma concentrations fall below 0.2 mg/dL, whereas the normal plasma concentration range is 0.4 to 1.5 mg/dL.

Fat-soluble vitamins

Vitamin Symptoms & Diagnosis Information
Vitamin A deficiency Can cause nyctalopia (night blindness) and keratomalacia, the latter leading to permanent blindness if not treated. The normal range is 30 to 65 μg/dL, but plasma concentrations within the range are not a good indicator of a pending deficiency because the normal range is sustained until liver storage is depleted. After that happens, plasma retinol concentration falls to lower than 20 μg/dL, signifying a state of vitamin A inadequacy. It is the leading cause of preventable childhood blindness, afflicting 250,000 to 500,000 malnourished children in the developing world each year, about half of whom die within a year of becoming blind, as vitamin A deficiency also weakens the immune system.
Vitamin D deficiency Usually asymptomatic, causes reduce bone density associated with the development of schizophrenia. It is typically diagnosed by measuring the concentration of the 25-hydroxyvitamin D (25(OH)D) in plasma, which is the most accurate measure of stores of vitamin D in the body. Deficiency is defined as less than 10 ng/mL, and insufficiency in the range of 10–30 ng/mL. Serum 25(OH)D concentrations above 30 ng/mL are "not consistently associated with increased benefit." Serum concentrations above 50 ng/mL may be cause for concern. Common, most foods do not contain vitamin D, indicating that a deficiency will occur unless people get sunlight exposure or eat manufactured foods purposely fortified with vitamin D. Vitamin D deficiency is a known cause of rickets, and has been linked to numerous other health problems.
Vitamin E deficiency Causes poor conduction of electrical impulses along nerves due to changes in nerve membrane structure and function. The US Institute of Medicine defines deficiency as a blood concentration of less than 12 μmol/L. Rare, occurring as a consequence of abnormalities in dietary fat absorption or metabolism, such as a defect in the alpha-tocopherol transport protein, rather than from a diet low in vitamin E.
Vitamin K deficiency Signs and symptoms can include sensitivity to bruising, bleeding gums, nosebleeds, and heavy menstrual bleeding in women. Rare as consequence of low dietary intake. A deficient state can be a result of fat malabsorption diseases. Newborn infants are a special case. Plasma vitamin K is low at birth, even if the mother is supplemented during pregnancy, because the vitamin is not transported across the placenta. Vitamin K deficiency bleeding (VKDB) due to physiologically low vitamin K plasma concentrations is a serious risk for premature and term newborn and young infants. Untreated, consequences can cause brain damage or death. The prevalence of VKDB is reported at 0.25 to 1.7%, with higher risk in Asian populations. The recommended prevention treatment is an intramuscular injection of 1 mg of vitamin K at birth (called the Vitamin K shot.). There are protocols for oral administration, but intramuscular injection is preferred.

Prevention

Food fortification

Food fortification is the process of adding micronutrients (essential trace elements and vitamins) to food as a public health policy which aims to reduce the number of people with dietary deficiencies within a population. Staple foods of a region can lack particular nutrients due to the soil of the region or from inherent inadequacy of a normal diet. Addition of micronutrients to staples and condiments can prevent large-scale deficiency diseases in these cases.

As defined by the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), fortification refers to "the practice of deliberately increasing the content of an essential micronutrient, i.e., vitamins and minerals in a food irrespective of whether the nutrients were originally in the food before processing or not, so as to improve the nutritional quality of the food supply and to provide a public health benefit with minimal risk to health", whereas enrichment is defined as "synonymous with fortification and refers to the addition of micronutrients to a food which are lost during processing". The Food Fortification Initiative lists all countries in the world that conduct fortification programs, and within each country, what nutrients are added to which foods. Vitamin fortification programs exist in one or more countries for folate, niacin, riboflavin, thiamin, vitamin A, vitamin B6, vitamin B12, vitamin D and vitamin E. As of 21 December 2018, 81 countries required food fortification with one or more vitamins. The most commonly fortified vitamin – as used in 62 countries – is folate; the most commonly fortified food is wheat flour.

Genetic engineering

Starting in 2000, rice was experimentally genetically engineered to produce higher than normal beta-carotene content, giving it a yellow/orange color. The product is referred to as golden rice (Oryza sativa). Biofortified sweet potato, maize, and cassava were other crops introduced to enhance the content of beta-carotene and certain minerals.

When eaten, beta-carotene is a provitamin, converted to retinol (vitamin A). The concept is that in areas of the world where vitamin A deficiency is common, growing and eating this rice would reduce the rates of vitamin A deficiency, particularly its effect on childhood vision problems. As of 2018, fortified golden crops were still in the process of government approvals, and were being assessed for taste and education about their health benefits to improve acceptance and adoption by consumers in impoverished countries.

Hypervitaminosis

Some vitamins cause acute or chronic toxicity, a condition called hypervitaminosis, which occurs mainly for fat-soluble vitamins if over-consumed by excessive supplementation. Hypervitaminosis A and hypervitaminosis D are the most common examples. Vitamin D toxicity does not result from sun exposure or consuming foods rich in vitamin D, but rather from excessive intake of vitamin D supplements, possibly leading to hypercalcemia, nausea, weakness, and kidney stones.

The United States, European Union and Japan, among other countries, have established "tolerable upper intake levels" for those vitamins which have documented toxicity.

History

The discovery dates of vitamins and their sources
Year of discovery Vitamin
1913 Vitamin A (Retinol)
1910 Vitamin B1 (Thiamine)
1920 Vitamin C (Ascorbic acid)
1920 Vitamin D (Calciferol)
1920 Vitamin B2 (Riboflavin)
1922 Vitamin E (Tocopherol)
1929 Vitamin K1 (Phylloquinone)
1931 Vitamin B5 (Pantothenic acid)
1931 Vitamin B7 (Biotin)
1934 Vitamin B6 (Pyridoxine)
1936 Vitamin B3 (Niacin)
1941 Vitamin B9 (Folate)
1948 Vitamin B12 (Cobalamins)

In 1747, the Scottish surgeon James Lind discovered that citrus foods helped prevent scurvy, a particularly deadly disease in which collagen is not properly formed, causing poor wound healing, bleeding of the gums, severe pain, and death. In 1753, Lind published his Treatise on the Scurvy, which recommended using lemons and limes to avoid scurvy, which was adopted by the British Royal Navy. This led to the nickname limey for British sailors. Lind's discovery, however, was not widely accepted by individuals in the Royal Navy's Arctic expeditions in the 19th century, where it was widely believed that scurvy could be prevented by practicing good hygiene, regular exercise, and maintaining the morale of the crew while on board, rather than by a diet of fresh food.

During the late 18th and early 19th centuries, the use of deprivation studies allowed scientists to isolate and identify a number of vitamins. Lipid from fish oil was used to cure rickets in rats, and the fat-soluble nutrient was called "antirachitic A". Thus, the first "vitamin" bioactivity ever isolated, which cured rickets, was initially called "vitamin A"; however, the bioactivity of this compound is now called vitamin D. In 1881, Russian medical doctor Nikolai I. Lunin studied the effects of scurvy at the University of Tartu. He fed mice an artificial mixture of all the separate constituents of milk known at that time, namely the proteins, fats, carbohydrates, and salts. The mice that received only the individual constituents died, while the mice fed by milk itself developed normally. He made a conclusion that substances essential for life must be present in milk other than the known principal ingredients. However, his conclusions were rejected by his advisor, Gustav von Bunge.

In East Asia, where polished white rice was the common staple food of the middle class, beriberi resulting from lack of vitamin B1 was endemic. In 1884, Takaki Kanehiro, a British-trained medical doctor of the Imperial Japanese Navy, observed that beriberi was endemic among low-ranking crew who often ate nothing but rice, but not among officers who consumed a Western-style diet. With the support of the Japanese Navy, he experimented using crews of two battleships; one crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice, and beans. The group that ate only white rice documented 161 crew members with beriberi and 25 deaths, while the latter group had only 14 cases of beriberi and no deaths. This convinced Takaki and the Japanese Navy that diet was the cause of beriberi, but they mistakenly believed that sufficient amounts of protein prevented it. That diseases could result from some dietary deficiencies was further investigated by Christiaan Eijkman, who in 1897 discovered that feeding unpolished rice instead of the polished variety to chickens helped to prevent beriberi. The following year, Frederick Hopkins postulated that some foods contained "accessory factors" — in addition to proteins, carbohydrates, fats etc. — that are necessary for the functions of the human body. Hopkins and Eijkman were awarded the Nobel Prize for Physiology or Medicine in 1929 for their discoveries.

Jack Drummond's single-paragraph article in 1920 which provided structure and nomenclature used today for vitamins

In 1910, the first vitamin complex was isolated by Japanese scientist Umetaro Suzuki, who succeeded in extracting a water-soluble complex of micronutrients from rice bran and named it aberic acid (later Orizanin). He published this discovery in a Japanese scientific journal. When the article was translated into German, the translation failed to state that it was a newly discovered nutrient, a claim made in the original Japanese article, and hence his discovery failed to gain publicity. In 1912 Polish-born biochemist Casimir Funk, working in London, isolated the same complex of micronutrients and proposed the complex be named "vitamine". It was later to be known as vitamin B3 (niacin), though he described it as "anti-beri-beri-factor" (which would today be called thiamine or vitamin B1). Funk proposed the hypothesis that other diseases, such as rickets, pellagra, coeliac disease, and scurvy could also be cured by vitamins. Max Nierenstein, a friend and reader of Biochemistry at Bristol University, reportedly suggested the "vitamine" name (from "vital amine"). The name soon became synonymous with Hopkins' "accessory factors", and by the time it was shown that not all vitamins are amines the word was already ubiquitous. In 1920, Jack Cecil Drummond proposed that the final "e" be dropped to deemphasize the "amine" reference, after researchers began to suspect that not all "vitamines" (in particular, vitamin A) have an amine component.

In 1930, Paul Karrer elucidated the correct structure for beta-carotene, the main precursor of vitamin A, and identified other carotenoids. Karrer and Norman Haworth confirmed Albert Szent-Györgyi's discovery of ascorbic acid and made significant contributions to the chemistry of flavins, which led to the identification of lactoflavin. For their investigations on carotenoids, flavins and vitamins A and B2, Karrer and Haworth jointly received the Nobel Prize in Chemistry in 1937. In 1931, Albert Szent-Györgyi and a fellow researcher Joseph Svirbely suspected that "hexuronic acid" was actually vitamin C, and gave a sample to Charles Glen King, who proved its anti-scorbutic activity in his long-established guinea pig scorbutic assay. In 1937, Szent-Györgyi was awarded the Nobel Prize in Physiology or Medicine for this discovery. In 1938, Richard Kuhn was awarded the Nobel Prize in Chemistry for his work on carotenoids and vitamins, specifically B2 and B6. In 1943, Edward Adelbert Doisy and Henrik Dam were awarded the Nobel Prize in Physiology or Medicine for their discovery of vitamin K and its chemical structure. In 1967, George Wald was awarded the Nobel Prize in Physiology or Medicine (jointly with Ragnar Granit and Haldan Keffer Hartline) for the discovery that vitamin A could participate directly in a physiological process.

Neural tube defect

From Wikipedia, the free encyclopedia
 
Neural tube defect
Spina-bifida.jpg
Illustration of a child with spina bifida, the most common NTD
SpecialtyMedical genetics

Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embryo begin to change shape and form the neural tube. When the neural tube does not close completely, an NTD develops.

Specific types include: spina bifida which affects the spine, anencephaly which results in little to no brain, encephalocele which affects the skull, and iniencephaly which results in severe neck problems.

NTDs are one of the most common birth defects, affecting over 300,000 births each year worldwide. For example, spina bifida affects approximately 1,500 births annually in the United States, or about 3.5 in every 10,000 (0.035% of US births), which has decreased from around 5 per 10,000 (0.05% of US births) since folate fortification of grain products was started. The number of deaths in the US each year due to neural tube defects also declined from 1,200 before folate fortification was started to 840.

Types

There are two classes of NTDs: open, which are more common, and closed. Open NTDs occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae (spinal column). Open NTDs include anencephaly, encephaloceles, hydranencephaly, iniencephaly, schizencephaly, and the most common form, spina bifida. Closed NTDs occur when the spinal defect is covered by skin. Types of closed NTDs include lipomeningocele, lipomyelomeningocele, and tethered cord.

Anencephaly

Anencephaly (without brain) is a severe neural tube defect that occurs when the anterior-most end of the neural tube fails to close, usually during the 23rd and 26th days of pregnancy. This results in an absence of a major portion of the brain and skull. Infants born with this condition lack the main part of the forebrain and are usually blind, deaf and display major craniofacial anomalies. The lack of a functioning cerebrum will prevent the infant from even gaining consciousness. Infants are either stillborn or usually die within a few hours or days after birth. For example, anencephaly in humans can result from mutations in the NUAK2 kinase.

Encephaloceles

Encephaloceles are characterized by protrusions of the brain through the skull that are sac-like and covered with membrane. They can be a groove down the middle of the upper part of the skull, between the forehead and nose, or the back of the skull. Due to the range in its location, encephaloceles are classified by the location as well as the type of defect it causes. Subtypes include occipital encephalocele, encephalocele of the carnival vault, and nasal encephaloceles (frontoethmoidal encephaloceles and basal encephaloceles), with approximately 80% of all encephaloceles occurring in the occipital area. Encephaloceles are often obvious and diagnosed immediately. Sometimes small encephaloceles in the nasal and forehead are undetected. Despite the wide range in its implications, encephaloceles are most likely to be caused by improper separation of the surface ectoderm and the neuroectoderm after the closure of the neural folds in the fourth week of gastrulation.

Hydranencephaly

Hydranencephaly is a condition in which the cerebral hemispheres are missing and instead filled with sacs of cerebrospinal fluid. People are born with hydranencephaly, but most of the time, the symptoms appear in a later stage. Newborns with hydrancephaly can swallow, cry, sleep and their head is in proportion to their body. However, after a few weeks, the infants develop increased muscle tone and irritability. After a few months, the brain start to fill with cerebrospinal fluid (hydrocephalus). This has several consequences. Infants start to develop problems with seeing, hearing, growing, and learning. The missing parts of the brain and the amount of cerebrospinal fluid can also lead to seizures, spasm, problems with regulating their body temperature, and breathing and digestion problems. Besides problems in the brain, hydranencephaly can also be seen on the outside of the body. Hydrocephalus leads to more cerebrospinal fluid in the brain, which can result in an enlarged head.

The cause of hydranencephaly is not clear. Hydranencephaly is a result of an injury of the nervous system or an abnormal development of the nervous system. The neural tube closes in the sixth week of the pregnancy, so hydranencephaly develops during these weeks of the pregnancy. The cause of these injuries/development is not clear.

Theories regarding the causes of hydrancephaly include:

  • blockage in the carotid artery: some researchers think that a blockage of the carotid artery leads to the under-/no development of the brain. The carotid artery is the most important blood supplier of the brain. With a blockage, the brain barely receives blood. Blood is necessary for development and keeping intact of the brain.
  • inherited condition.
  • infections: during the pregnancy, a woman can develop an infection in the uterus what can lead to problems with the neural tube.
  • environmental toxins: during the pregnancy, a woman can be exposed to environmental toxins what can have effect on the health of the infant.

Iniencephaly

Iniencephaly is a rare neural tube defect that results in extreme bending of the head to the spine. The diagnosis can usually be made on antenatal ultrasound scanning, but if not will undoubtedly be made immediately after birth because the head is bent backwards and the face looks upwards. Usually the neck is absent. The skin of the face connects directly to the chest and the scalp connects to the upper back. Individuals with iniencephaly generally die within a few hours after birth.

Spina bifida

Spina bifida is further divided into two subclasses, spina bifida cystica and spina bifida occulta.

  • Spina bifida cystica includes meningocele and myelomeningocele. Meningocele is less severe and is characterized by herniation of the meninges, but not the spinal cord, through the opening in the spinal canal. Myelomeningocele involves herniation of the meninges as well as the spinal cord through the opening.
  • Spina bifida occulta means hidden split spine. In this type of neural tube defect, the meninges do not herniate through the opening in the spinal canal. The most frequently seen form of spina bifida occulta is when parts of the bones of the spine, called the spinous process, and the neural arch appear abnormal on a radiogram, without involvement of the spinal cord and spinal nerves. The risk of recurrence in those who have a first degree relative (a parent or sibling) is 5–10 times greater compared to the general population.

Causes

Folate deficiency

Inadequate levels of folate (vitamin B9) and vitamin B12 during pregnancy have been found to lead to increased risk of NTDs. Although both are part of the same biopathway, folate deficiency is much more common and therefore more of a concern. Folate is required for the production and maintenance of new cells, for DNA synthesis and RNA synthesis. Folate is needed to carry one carbon groups for methylation and nucleic acid synthesis. It has been hypothesized that the early human embryo may be particularly vulnerable to folate deficiency due to differences of the functional enzymes in this pathway during embryogenesis combined with high demand for post translational methylations of the cytoskeleton in neural cells during neural tube closure. Failure of post-translational methylation of the cytoskeleton, required for differentiation has been implicated in neural tube defects. Vitamin B12 is also an important receptor in the folate biopathway such that studies have shown deficiency in vitamin B12 contributes to risk of NTDs as well. There is substantial evidence that direct folic supplementation increases blood serum levels of bioavailable folate even though at least one study have shown slow and variable activity of dihydrofolate reductase in human liver. A diet rich in natural folate (350 μg/d) can show as much increase in plasma folate as taking low levels of folic acid (250 μg/d) in individuals However a comparison of general population outcomes across many countries with different approaches to increasing folate consumption has found that only general food fortification with folic acid reduces neural tube defects. While there have been concerns about folic acid supplementation being linked to an increased risk for cancer, a systematic review in 2012 shows there is no evidence except in the case of prostate cancer which indicates a modest reduction in risk.

There have been studies showing the relationship between NTDs, folate deficiency and the difference of skin pigmentation within human populations across different latitudes. There are many factors that would influence the folate levels in human bodies: (i) the direct dietary intake of folic acid through fortified products, (ii) environmental agents such as UV radiation. In concern with the latter, the UV radiation-induced folate photolysis has been shown via in vitro and in vivo studies to decrease the folate level and implicate in etiology of NTDs not only in humans but other amphibian species. Therefore, a protection against the UV radiation-induced photolysis of folate is imperative for the evolution of human populations living in tropical regions where the exposure to UV radiation is high over the year. One body natural adaptation is to elevate the concentration of melanin inside the skin. Melanin works as either an optical filter to disperse the incoming UV radiation rays or free radical to stabilize the hazardous photochemical products. Multiple studies have demonstrated the highly melanized integument as a defense against folate photolysis in Native Americans or African Americans correlates with lower occurrence of NTDs in general.

Genetic deficiencies

As reported by Bruno Reversade and colleagues, the inactivation of the NUAK2 kinase in humans leads to anencephaly. This fatal birth defect is believed to arise as a consequence of impaired HIPPO signalling. Other genes such as TRIM36 have also been associated with anencephaly in humans.

Gene-environment interaction

A deficiency of folate itself does not cause neural tube defects. The association seen between reduced neural tube defects and folic acid supplementation is due to a gene-environment interaction such as vulnerability caused by the C677T methylenetetrahydrofolate reductase (MTHFR) variant. Supplementing folic acid during pregnancy reduces the prevalence of NTDs by not exposing this otherwise sub-clinical mutation to aggravating conditions. Other potential causes can include folate antimetabolites (such as methotrexate), mycotoxins in contaminated corn meal, arsenic, hyperthermia in early development, and radiation. Maternal obesity has also been found to be a risk factor for NTDs. Studies have shown that both maternal cigarette smoking and maternal exposure to secondhand smoke increased the risk for neural tube defects in offspring. A mechanism by which maternal exposure to cigarette smoke could increase NTD risk in offspring is suggested by several studies that show an association between cigarette smoking and elevations of homocysteine levels. Cigarette smoke during pregnancy, including secondhand exposure, can increase the risk of neural tube defects. All of the above may act by interference with some aspect of normal folic acid metabolism and folate linked methylation related cellular processes as there are multiple genes of this type associated with neural tube defects.

Other

Folic acid supplementation reduces the prevalence of neural tube defects by approximately 70% of neural tube defects indicating that 30% are not folate-dependent and are due to some cause other than alterations of methylation patterns. Multiple other genes related to neural tube defects exist which are candidates for folate insensitive neural tube defects. There are also several syndromes such as Meckel syndrome, and triploid syndrome which are frequently accompanied by neural tube defects that are assumed to be unrelated to folate metabolism

Diagnosis

Tests for neural tube defects include ultrasound examination and measurement of maternal serum alpha-fetoprotein (MSAFP). Second trimester ultrasound is recommended as the primary screening tool for NTDs, and MSAFP as a secondary screening tool. This is due to increased safety, increased sensitivity and decreased false positive rate of ultrasound as compared to MSAFP. Amniotic fluid alpha-fetoprotein (AFAFP) and amniotic fluid acetylcholinesterase (AFAChE) tests are also used to confirming if ultrasound screening indicates a positive risk. Often, these defects are apparent at birth, but acute defects may not be diagnosed until much later in life. An elevated MSAFP measured at 16–18 weeks gestation is a good predictor of open neural tube defects, however the test has a very high false positive rate, (2% of all women tested in Ontario, Canada between 1993 and 2000 tested positive without having an open neural tube defect, although 5% is the commonly quoted result worldwide) and only a portion of neural tube defects are detected by this screen test (73% in the same Ontario study). MSAFP screening combined with routine ultrasonography has the best detection rate although detection by ultrasonography is dependent on operator training and the quality of the equipment.

Prevention

Incidence of neural tube defects has been shown to decline through maintenance of adequate folic acid levels prior to and during pregnancy. This is achieved through dietary sources and supplementation of folic acid. In 1996, the United States Food and Drug Administration published regulations requiring the addition of folic acid to enriched breads, cereals, flour and other grain products. Similar regulations made it mandatory to fortify selected grain products with folic acid in Canada by 1998. It is important to note that during the first four weeks of pregnancy (when most people do not even realize that they are pregnant), adequate folate intake is essential for proper operation of the neurulation process. Therefore, any individuals who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risks of serious birth defects. In Canada, mandatory fortification of selected foods with folic acid had been shown to reduce the incidence of neural tube defects by 46% compared to incidence prior to mandatory fortification. However, relying on eating a folate-rich diet alone is not recommended for preventing neural tube defects when trying to conceive because a regular diet usually does not contain enough folate to reach pregnancy requirements. All individuals who have the ability to become pregnant are advised to get 400 micrograms of folic acid daily. This daily 400 mcg dose of folic acid can be found in most multivitamins advertised as for women. Higher doses can be found in pre-natal multivitamins but those doses may not be necessary for everyone. Individuals who have previously given birth to a child with a neural tube defect and are trying to conceive again may benefit from a supplement containing 4.0 mg daily, following advice provided by their doctor. In Canada, guidelines on folic acid intake when trying to conceive is based on a risk assessment of how likely they are to experience a neural tube defect during pregnancy. Risk is divided into high, moderate, and low risk categories. High risk would include those that had a past experience with neural tube defects, either themselves or during another pregnancy. Medium risk individuals are those with certain conditions that put them at higher risk for experiencing a neural tube defect. These include having a first or second degree relative or partner with a history of neural tube defects, having a gastrointestinal condition that affects normal absorption patterns, advanced kidney disease, kidney dialysis, alcohol over-use, or had another pregnancy resulting in a congenital abnormality that was folate sensitive. Medium risk individuals would also include those taking medications that can interfere with folate absorption such as anticonvulsants, metformin, sulfasalazine, triamterene, and trimethoprim. Low risk would include everyone else that do not fall into either medium or high risk categories. Recommendations on when to start folic acid supplementation for all individuals looking to become pregnant is at least 3 months preconception. If an individual is in the high risk category, the recommended dose is 4–5 mg of folic acid daily until 12 weeks gestation and then decrease to 0.4–1 mg until 4–6 weeks postpartum or for however long breastfeeding lasts. If an individual is in the medium risk category, the recommended dose is 1 mg of folic acid daily until 12 weeks gestation and then they can either continue at 1 mg or decrease to 0.4 mg daily until 4–6 weeks postpartum or however long breastfeeding lasts. If the pregnancy is low risk to develop a neural tube defect then the recommendation for that individual is 0.4 mg daily until 4–6 weeks postpartum or however long breastfeeding lasts. All dose recommendations and risk assessment should be done with the advice of a qualified health care provider.

Treatment

As of 2008, treatments of NTDs depends on the severity of the complication. No treatment is available for anencephaly and infants usually do not survive more than a few hours. Aggressive surgical management has improved survival and the functions of infants with spina bifida, meningoceles and mild myelomeningoceles. The success of surgery often depends on the amount of brain tissue involved in the encephalocele. The goal of treatment for NTDs is to allow the individual to achieve the highest level of function and independence. Fetal surgery in utero before 26 weeks gestation has been performed with some hope that there is benefit to the outcome including a reduction in Arnold–Chiari malformation and thereby decreases the need for a ventriculoperitoneal shunt but the procedure is very high risk for both mother and baby and is considered extremely invasive with questions that the positive outcomes may be due to ascertainment bias and not true benefit. Further, this surgery is not a cure for all problems associated with a neural tube defect. Other areas of research include tissue engineering and stem cell therapy but this research has not been used in humans.

Epidemiology

Deaths from neural tube defects per million persons in 2012
  0–0
  1–1
  2–3
  4–6
  7–10
  11–15
  16–20
  21–28
  29–69

Neural tube defects resulted in 71,000 deaths globally in 2010. It is unclear how common the condition is in low income countries.

Prevalence rates of NTDs at birth used to be a reliable measure for the actual number of children affected by the diseases. However, due to advances in technology and the ability to diagnose prenatally, the rates at birth are no longer reliable. Measuring the number of cases at birth may be the most practical way, but the most accurate way would be to include stillbirths and live-births. Most studies that calculate prevalence rates only include data from live births and stillborn children and normally exclude the data from abortions and miscarriages. Abortions are a huge contributing factor to the prevalence rates; one study found that in 1986 only a quarter of the pregnancies with an identified NTD were aborted, but that number had already doubled by 1999. Through this data, it is clear that excluding data from abortions could greatly affect the prevalence rates. This could also possibly explain why prevalence rates have appeared to drop. If abortions are not being included in the data but half of the identified cases are being aborted, the data could show that prevalence rates are dropping when they actually are not. However, it is unclear how much of an impact these could have on prevalence rates due to the fact that abortion rates and advances in technology vary greatly by country.

There are many maternal factors that also play a role in prevalence rates of NTDs. These factors include things like maternal age and obesity all the way to things like socioeconomic status along with many others. Maternal age has not been shown to have a huge impact on prevalence rates, but when there has been a relationship identified, older mothers along with very young mothers are at an increased risk. While maternal age may not have a huge impact, mothers that have a body mass index greater than 29 double the risk of their child having an NTD. Studies have also shown that mothers with three or more previous children show moderate risk for their next child having an NTD.

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