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Kwashiorkor – reflections on the ‘revisiting the evidence’ series

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By Merry Fitzpatrick, Gerard Bryan Gonzales, Alexandra Rutishauser-Perera and André Briend

Merry Fitzpatrick is a Researcher Assistant Professor at the Feinstein International Center, Tufts University.

Gerard Bryan Gonzales is an Assistant Professor in the Division of Human Nutrition and Health, Wageningen University and Research.

Alexandra Rutishauser-Perera is Head of Nutrition at Action Against Hunger UK.

André Briend is an Adjunct Professor at University of Tampere.

The authors would also like to acknowledge James A Berkley (FRCPCH FMedSci), Robert Bandsma (MD, PhD) and Asha Badaloo (BSc, MSc, PhD) who presented at the webinars thereby contributing to this article.

The full recordings of the webinar series can be found at https://fic.tufts.edu/research-item/revisiting-the-evidence-on-kwashiorkor-malnutrition/

Background

In 1968, a collection of kwashiorkor researchers and practitioners gathered in Cambridge, Massachusetts for a colloquium to discuss the evidence relating to kwashiorkor. Attendees shared their experiences, understanding and research findings. The merits of the evidence were discussed and debated and a diagnostic criteria for kwashiorkor was determined – bipedal pitting oedema – that remains the primary diagnostic criteria for classifying kwashiorkor today, 50 years later.

Following in the footsteps of these researchers, an informal working group comprised of a new generation of kwashiorkor researchers and practitioners has formed to support each other in the continuing quest to improve the understanding and treatment of kwashiorkor. Members share journal articles, discuss findings and share opinions on points within the evidence. The researchers also discuss their research struggles and help each other with study designs, occasionally collaborating on studies and proposals. Encouraged and supported by the engagement of this working group, several members worked together to initiate a series of webinars to review the current evidence on kwashiorkor and to identify gaps in the evidence.

Three webinars were held towards the end of 2020 covering the following topics: 1) the basic characterisation and treatment of kwashiorkor, 2) observable signs of kwashiorkor and 3) metabolic and biochemical characterisation of kwashiorkor.1 Three more webinars are planned for the spring of 2021 and, later in the year (pandemic permitting), we hope to host a public day-long seminar. This will include presentations of the most recent research followed by a discussion with invited researchers to identify research priorities and consider the gaps in current treatment protocols. The group will together determine if sufficient evidence now exists to support diagnostic criteria for moderate kwashiorkor, allowing practitioners to catch cases of kwashiorkor before they progress to severe acute malnutrition with a high risk of mortality. The aim of this article is to reflect on the purpose of these discussions, the webinars covered so far and the next steps to garner interest among Field Exchange readers to engage with this important topic.

What is kwashiorkor and why is it important to understand it better?

Kwashiorkor is one of two major classifications of severe acute malnutrition. While marasmus is characterised by low weight-for-height, kwashiorkor is diagnosed by bipedal pitting oedema. Other associated signs include pale and brittle hair, skin lesions, lethargy and a fatty liver as well as numerous metabolic anomalies.

Figure 1: Peer reviewed articles referring to ‘kwashiorkor’ or ‘edematous malnutrition’ published per year from 1930 to 2020

Source: Data search from the PubMed website using the terms ‘kwashiorkor’ and ‘edematous malnutrition’ (National Library of Medicine 2021)

More than 4000 articles have been published on kwashiorkor since Cicely Williams introduced the name for this unique syndrome in the 1930s but only a small portion of these articles have been published in the past 40 years (Figure 1). Older publications are primarily descriptive and most recent studies are observational comparisons. Although data on kwashiorkor is slowly accumulating, only 10 clinical trials specific to kwashiorkor have been conducted, making it impossible to determine causality among all the observed phenomena associated with cases of kwashiorkor. The aetiology of kwashiorkor therefore remains elusive.

Despite its long history, the prevention and treatment of kwashiorkor still relies on very little solid evidence. Not only has research on kwashiorkor languished, no treatment specific to kwashiorkor has been developed and cases of kwashiorkor receive treatment designed to treat marasmus. Although these treatments do support the recovery of children with kwashiorkor, the very different metabolic anomalies and low circulating levels of key amino acids seen in kwashiorkor, even after resolution of oedema, indicate that adjustments to treatment would likely improve both short and long-term outcomes. 

Global prevalence of kwashiorkor is difficult to establish. Regardless of the very different metabolic and clinical differences in marasmus and kwashiorkor, studies of acute malnutrition and national nutrition surveys continue to either aggregate kwashiorkor with marasmus or exclude it altogether. Furthermore, normal nutritional surveys to estimate prevalence are poorly designed for the capturing of acute conditions such as kwashiorkor because children with kwashiorkor either die or spontaneously recover in a much shorter time than children with marasmus who may linger in a chronic state of wasting. This exaggerates the differences in the numbers of children with marasmus in comparison to children with kwashiorkor.

Survey teams are also often poorly trained to detect or characterise kwashiorkor. More recently, evaluation of family mid-upper arm circumference (MUAC) programmes reveal that most parents forget to check the presence of oedema when checking the nutrition status of their children (Lort-Phillips & Macias, 2016). Hence, reports on the incidence or prevalence of kwashiorkor are believed to underestimate the scale of the problem. The figures that are available indicate that hundreds of thousands of children are affected and at least tens of thousands die annually (Alvarez et al., 2016). Kwashiorkor tends to cluster in specific regions and communities meaning that aggregate figures hide areas where kwashiorkor prevalence is alarmingly high (Fitzpatrick et al., 2018; Fonaroff, 1969; Annegers, 1973; Kamalu, 1993). Most concerning is that areas where we know kwashiorkor is the most common type of acute malnutrition, but where prevalence data is poor, are areas where nutritional treatment programmes are also all but non-existent.

The lack of prevalence and incidence data is important because it allows the problem to be ignored. In a self-reinforcing negative cycle, with less visibility and understanding about the aetiology of kwashiorkor and its global prevalence, the condition receives less policy attention and guidance. For example, kwashiorkor was not included in the recent Global Nutrition Report and is not even mentioned on its website2 and the 2008 and 2013 Lancet Maternal Child Nutrition Series, which has dominated the formation of nutrition policy over the past 13 years, also did not include any reference to kwashiorkor (Lancet, 2008; Lancet, 2013). When this was pointed out to the authors, their response was there was insufficient evidence of the scale of the problem to include it in the policy priorities.

With the availability of new technologies, we now have the opportunity to review a growing body of evidence, identify the gaps in evidence and design better studies to fully unravel the aetiology and pathophysiology of kwashiorkor and promote surveillance that captures the global scale of the problem. In doing so, we will enable the development of better treatment protocols and prevention strategies which will help to reduce the burden of kwashiorkor and improve the clinical outcomes of hundreds of thousands of affected children each year.

What has been covered in the webinars so far?

The diagnosis of kwashiorkor remains largely based on the observation of oedema. However, many other clinical signs accompany, or may even precede, the development of oedema such as lethargy, loss of appetite, behavioural changes, skin lesions and fatty liver. This therefore indicates that oedema may be a late sign of kwashiorkor and its pathophysiology may be better understood by also considering the other signs of the disease.

The 2019 World Health Organization (WHO) International Classification of Disease defines kwashiorkor as a “form of severe malnutrition with nutritional oedema with dyspigmentation of skin and hair”3. Skin changes in kwashiorkor have been described for as long as oedema has. However, skin dyspigmentation and hair changes are often missed because the changes can be subtle, requiring skill to detect, and/or require a longer time to manifest. The aetiology of the skin changes is unknown and its relation to other clinical outcomes, especially mortality, is poorly documented. Hence, standardised global assessment of skin characteristics in severe acute malnutrition is required to obtain credible data that may be used to optimise treatment protocols. A tool for grading skin changes, SCORDoK (Scoring of skin changes in severe acute malnutrition) developed by the Department of Dermatology at the Aarhus University Hospital in Denmark, was presented at this webinar. Tools such as SCORDoK may be used to standardise the registration of skin changes in severe acute malnutrition, a necessary first step in building the evidence on relationships between skin changes and kwashiorkor. However, the utility and translatability of SCORDoK in other settings remains to be demonstrated.

The severity of oedema is the main criteria for admission and discharge while other signs such as the treatment of dehydration and skin lesions in kwashiorkor remain largely unoptimised. Dehydration is a topic of contention and conflicting opinions exist on rehydration protocols for children with kwashiorkor. Skin lesions may lead to infections and hypothermia, further endangering the health of already compromised individuals. Hence, management of skin changes in kwashiorkor is important but seldom included in treatment protocols. The integration of a holistic approach, including wound care and pain management, is essential. However, evidence so far of effective treatment strategies has been very heterogenous or scarce and largely built upon expert opinion rather than strong evidence-based research.

The difficulty in the diagnosis and treatment of kwashiorkor stems from our lack of understanding of its aetiology. The role of diet, specifically protein deficiency, has been the most popularly described mechanism for the development of kwashiorkor but the results of studies on diets estimating total dietary protein have not been consistent. However, many kwashiorkor study designs start with the assumption that decisive evidence has shown there is no quantitative difference in the diets of children developing kwashiorkor and those developing marasmus. This is based on a misinterpretation of a much-disputed study conducted by Gopalan in 1967 for which the data was never published (Gopalan, 1968). While some more recent studies using food frequency measures have also failed to find a difference (Kismul, Van den Broeck & Lunde, 2014; Lin et al., 2007; Sullivan et al., 2006), two studies that conducted more rigorous quantitative dietary recalls reported that children with kwashiorkor had consumed diets with less protein than children developing marasmus in the same environment (Gupte, 1975; Gupte & Mehta, 1971). A fresh look at the evidence indicates we should not dismiss diet as a major contributing cause of kwashiorkor and any new quantitative dietary research should examine the intake of individual amino acids instead of total protein.

Unravelling the aetiology of kwashiorkor also requires a deep understanding of the biochemical and metabolic perturbations that these children experience, especially in comparison to marasmus. Metabolism of kwashiorkor has been reported to differ from marasmus on several fronts. Protein and lipid oxidation are reduced in kwashiorkor compared to marasmus although these results were observed in the postabsorptive state, where circulating insulin levels are low, thereby affecting both lipid and carbohydrate metabolism. Studies in fed states, which may provide deeper insights into the differences in lipid and carbohydrate metabolism between kwashiorkor and marasmus, are however lacking. Tracing studies performed earlier in Jamaica also indicated an increased demand for sulphur-containing amino acids, cysteine and methionine, in the early rehabilitation phase of kwashiorkor. There is therefore a consensus that the metabolism of kwashiorkor is different from that of marasmus and characterising these as similar diseases is not appropriate and will not be helpful in improving current rehabilitation guidelines. However, despite interesting findings, these studies are observational and did not test causation using randomised controlled trials (RCTs).

One aspect that will benefit from well-designed RCTs is modified therapeutic foods (F75 and ready-to-use therapeutic food) that specifically address the metabolic requirements in kwashiorkor. For instance, apart from reduced protein and lipid oxidation, liver fat accumulation has been observed to be more prevalent among kwashiorkor than marasmus. There is therefore a basis to question whether children with kwashiorkor will benefit more from a rehabilitation food designed to meet their specific metabolic needs. For example, a very small trial showed the faster disappearance of oedema with the addition of cysteine to treatment (Badaloo et al., 2002). On the other hand, promoting a specialised treatment package for kwashiorkor may increase the logistical hurdles and cost, thereby reducing the coverage of rehabilitation programmes. More research is therefore needed to find cost-effective strategies to address kwashiorkor-specific metabolic perturbations.

There is also an ongoing debate as to the role of serum albumin concentration in the oedema associated with kwashiorkor. Oedema is the result of the expansion of the interstitial sector and could be explained by an excessive net transfer of fluid from the vascular system to the interstitial sector. The Starling principle4 describes how fluid movement across the capillary membrane depends on the balance between hydrostatic and oncotic pressures on both sides of this membrane. This principle is based on standard physical laws. When the albumin level is reduced, this has an effect on plasma oncotic pressure and leads to an increase of fluid transfer from the vascular to the interstitial sector (Starling, 1896). There are, however, several factors unrelated to Starling’s principle that influence the volume of the interstitial sector. For one, the lymphatic system drains fluid from the interstitial sector back to the plasma using an active mechanism of pumping fluid by lymphatic vessels. This has a major role in regulating the volume of the interestitial sector independently from fluid movement across the capillary membrane. As a result, it is not clear how important albumin is as a determinant of oedema.

Although a causal association remains to be fully demonstrated, there is general agreement that there is an association between kwashiorkor and low serum albumin; nevertheless, many children with low serum albumin concentration do not develop oedema and some adults with ascites and oedema have normal albumin concentrations. More basic research needs to be undertaken on albumin-dependent and -independent mechanisms that drive oedema formation.

Lastly, most of the reports on kwashiorkor rely on cross-sectional observations that attempt to explain a snapshot of a highly dynamic process. Therefore, capturing this dynamic process, either by observing determinants of kwashiorkor before it occurs or by subjecting children with kwashiorkor to a metabolic nudge and monitoring their response, may provide deeper insights into the pathophysiology, or perhaps aetiology, of kwashiorkor. In conclusion, there is still much more we do not know about kwashiorkor and more research, especially targeting mechanistic pathways, is necessary to elucidate the aetiology of this disease.

Details of the upcoming webinars will be announced on the ENN website and the Kwashiorkor: Revisiting the Evidence Webinar website at https://fic.tufts.edu/event/kwash-series/. We hope you will join us.

For more information, please contact Merry Fitzpatrick at merry.fitzpatrick@tufts.edu


1 Recordings of the webinars can be found on: https://fic.tufts.edu/research-item/revisiting-the-evidence-on-kwashiorkor-malnutrition/.

2 https://globalnutritionreport.org/reports/2020-global-nutrition-report 

3 https://icd.who.int/browse10/2019/en#/E40

4 Starling’s hypothesis, not to be confused with Starling’s principle, states that fluid flows from the capillary into the interestitial sector at the arterial end of the capillary and flows from the interstitial sector into the capillary at its venous end (Starling 1896).  While Starling’s principle remains unquestioned, recent evidence shows Starling’s hypothesis is no longer tenable (though it still remains in many textbooks) (Michel 2004). 


References

Alvarez, J L, Dent, N, Brown, Mark Myatt, M and Briend, A (2016) Putting Child Kwashiorkor on the Map. In CMAM Forum Technical Brief.

Annegers, J F (1973) The protein-calorie ratio of West African diets and their relationship to protein calorie malnutrition.  Ecology of Food and Nutrition 2 (3):225-235. doi: 10.1080/03670244.1973.9990340.

Badaloo, A, Reid, M, Forrester, T, Heird, W C and Jahoor F (2002) Cysteine supplementation improves the erythrocyte glutathione synthesis rate in children with severe edematous malnutrition.  The American Journal of Clinical Nutrition 76 (3):646-652.

Fitzpatrick, M,  Ghosh, S, Kurpad, A, Duggan, C and Maxwell, D (2018) Lost in Aggregation: The Geographic Distribution of Kwashiorkor in Eastern Democratic Republic of the Congo.  Food and Nutrition Bulletin. doi: 10.1177/0379572118794072.

Fonaroff, L S (1969) Settlement typology and infant malnutrition in Jamaica.  Tropical and Geographical Medicine 21:177-185.

Gopalan, C (1968) Kwashiorkor and Marasmus: Evolution and Distinguishing Features. In Calorie Deficiencies and Protein Deficiencies: Proceedings of a Colloquium held in Cambridge April 1967, edited by R.A. McCance and Elsie M. Widdowson, 49-58. Boston: Little, Brown and Company.

Gupte, S (1975) Marasmus and Kwashiorkor.  Pediatrics 56 (1):152-152.

Gupte, S and Mehta, S (1971) Advanced Protein-Calorie Malnutrition; Clinical observations on North Indian children.  Pediatric Clinics of India 5:91-100.

Kamalu, B P (1993) Cassava (Manihot Esculenta Crantz) in the Aetiology of Kwashiorkor.  Nutrition Research Reviews 6 (01):121-135. doi: doi:10.1079/NRR19930009.

Hallgeir, K, Van den Broeck, J and Markussen Lunde,  T (2014) Diet and kwashiorkor: a prospective study from rural DR Congo.  PeerJ 2:e350. doi: 10.7717/peerj.350.

Lin, C A, Boslaugh, S, Ciliberto, H M, Maleta, K, Ashorn, P, Briend, A and Manary, M J (2007) A Prospective Assessment of Food and Nutrient Intake in a Population of Malawian Children at Risk for Kwashiorkor.  Journal of Pediatric Gastroenterology and Nutrition 44 (4):487-493.

Lort-Phillips, H and Macias, D (2016) Enquête SLEAC du programme PECMAS et étude sur l’impact du projet pilote « PB Mamans ». In Renforcement de la lutte contre la malnutrition aigüe sévère et de sa prise en charge au Sénégal par une approche multisectorielle et

intégrée dans la région de Matam, Sénégal. Matam, Senegal: Action Against Hunger UK.

Michel, C C (2004) Fluid exchange in the microcirculation.  J Physiol 557 (Pt 3):701-2. doi: 10.1113/jphysiol.2004.063511.

National Library of Medicine (2021) "PubMed." accessed 2 April 2021. https://pubmed-ncbi-nlm-nih-gov.ezproxy.library.tufts.edu/advanced/.

Starling, E H (1896) On the Absorption of Fluids from the Connective Tissue Spaces.  J Physiol 19 (4):312-26. doi: 10.1113/jphysiol.1896.sp000596.

Sullivan, J, MacDonald, N, Maker, D, Hotz, C and Manary, M J (2006) The quality of the diet in Malawian children with kwashiorkor and marasmus.  Maternal & Child Nutrition 2 (2):114-122. doi: 10.1111/j.1740-8709.2006.00053.x.

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Merry Fitzpatrick, Gerard Bryan Gonzales, Alexandra Rutishauser-Perera and André Briend (). Kwashiorkor – reflections on the ‘revisiting the evidence’ series. Field Exchange 65, May 2021. p11. www.ennonline.net/fex/65/kwashiorkorworkinggroup

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