Protein energy malnutrition pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Omodamola Aje B.Sc, M.D. [2], Syed Hassan A. Kazmi BSc, MD [3]

## Overview

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Protein-energy malnutrition represents a shift of the body from fed to fasting/starvation state. Starvation leads to a decreased basal plasma insulin concentration and in decrease of glucose-stimulated insulin secretion. Prolonged fasting results in a deficiency in amino acids used for gluconeogenesis. It is thought that kwashiorkor is produced by a deficiency in the adequate consumption of protein-rich foods during the weaning process. However, the associated edema is not fully understood. Several theories have been put forward to explain this finding. Marasmus on the other hand is thought to be due to the total caloric deficiency leading to wastingin a child. Marasmus always results from a negative energy balance.

## Pathophysiology

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Several studies have shown that a deficiency in the consumption of protein, carbohydrates and fat is responsible for the development of protein-energy malnutrition. However, other studies have proposed that chronic infections such as helminthic infections are mainly responsible for the development of protein-energy malnutrition.[1] The underlying mechanisms include the following:

* Decreased food intake because of anorexia
* Decreased nutrient absorption
* Increased metabolic requirements
* Direct nutrient losses

The pathologic changes involved in protein-energy malnutrition include:[2]

* Immunologic deficiency in the humoral and cellular subsystem as a result of protein deficiency.
* Metabolic disturbances cause impaired intercellular degradation of fatty acids as a result of carbohydrate deficiency.
* Poor synthesis of pigments in the hair and skin is observed, with more frequency among children with low levels of zinc.

## Pathogenesis

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### Hormonal and molecular mechanisms (fed to starvation state)

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* Protein-energy malnutrition represents a shift of the body from fed to fasting/starvation state.
* The post-fed state may be considered as a useful reference point, as it denotes the period of metabolic transition from the fed to the fasted condition.
* Physiologically, the decrease in circulating insulin to postabsorptive levels results in a marked reduction of glucose uptake by peripheral insulin-dependent tissues (muscle and adipose tissues) and a shift toward utilization of fatty acids as energy currency.
* Glucose consumption continues by non-insulin dependent tissues (brain, renal medulla, and formed elements of the blood) and the splanchnic bed.
* The major site of glucose utilization is the brain, which depends completely upon a continuous supply of glucose for oxidative metabolism during pot-absorptive state.
* Maintenance of blood glucose balance is achieved by the hepatic production of glucose at rates equal to those of tissue utilization.

Insulin and glucagon in starvation

* Starvation leads to a decreased basal plasma insulin concentration and in decrease of glucose-stimulated insulin secretion. There is also an increase in counter-regulatory hormone concentration, for example, glucagon, cortisol and catecholamines in order to replete the glucose levels in the blood plasma.[3][4]
* In case of starvation, there is regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. In ketosis, the blood pH remains within normal limits.[5]

* The rate of lipolysis and ketogenesis depends upon the action of three enzymes:[5]
* Hormone-sensitive lipase (or triglyceride lipase), which is found in peripheral adipocytes
* Acetyl CoA carboxylase, which is found in the liver
* Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS), which is also found in the liver

* Insulin and glucagon play the key roles in regulating lipolysis and ketogenesis by acting in opposition to each other.
* Insulin inhibits ketogenesis by causing the dephosphorylation of hormone-sensitive lipase (HSL) and leads to lipogenesis by stimulating acetyl CoA carboxylase.[6]
* In the adipose tissue, dephosphorylation of hormone-sensitive lipase (HSL) decreases the degradation of triglycerides into fatty acids and glycerol, the rate-limiting step in the release of free fatty acids from the adipocyte. This subsequently reduces the amount of substrate that is available for ketogenesis.[7]
* Insulin also dephosphorylates the inhibitory sites on acetyl CoA carboxylase leading to enzyme activation and increased production of malonyl CoA. Malonyl CoA inhibitsbeta oxidation of fatty acids thereby decreasing ketogenesis.[7]
* Glucagon stimulates ketogenesis by causing the phosphorylation of both hormone-sensitive lipase (HSL) and acetyl CoA carboxylase via cyclic AMP-dependent protein kinase. In the adipocytes, phosphorylation of lipase by cyclic AMP-dependent protein kinase causes degradation of triglycerides into fatty acids.[8][9]
* In hepatocytes, phosphorylation of acetyl CoA carboxylase by cyclic AMP-dependent protein kinase decreases the production of malonyl CoA which subsequently stimulates fatty acid uptake by the mitochondria of the cells for oxidation, and thus increases the amount of substrate available for ketogenesis.
* The activity of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) is increased by starvation and a high-fat diet, and it is decreased by insulin.[10]

Eventual decreased gluconeogenesis in protein-energy malnutrition

* Prolonged fasting results in a deficiency in amino acids used for gluconeogenesis.
* Glucagon concentrations have been found to be lower in children with kwashiorkor compared with marasmus but similar to normal controls.[6]

Malnutrition, Leptin, and Immunity

* Leptin is a central mediator connecting nutrition and immunity.[7]
* Protein-energy malnutrition reduces leptin concentrations and increases serum levels of stress hormones, i.e., glucocorticoids.[8]
* Leptin concentrations are related to body adipose tissue and are rapidly reduced by fasting.
* Low leptin concentrations and glucocorticoids impair macrophage functions by decreasing NF-kB translocation into the nucleus.[9]

### Pathogenesis of marasmus

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* Marasmus results when subcutaneous fat and muscle are lost because of endogenous mobilization of all available energy and nutrients.
* The overall metabolic adaptations that occur during marasmus are similar to those in starvation.
* Initially, gluconeogenesis is triggered and aims at maintaining the energy requirements of the body leading to a perceived increase in metabolic rate.
* As fasting progresses, gluconeogenesis is suppressed to minimize muscle protein breakdown, and ketones derived from fat become the main fuel for the brain.
* One of the main adaptations to long-standing energy deficiency is a decreased rate of linear growth, leading to permanent stunting.

### Pathogenesis of edema in kwashiorkor

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Several theories have been postulated to explain the mechanism of edema seen in children with kwashiorkor. Some of them include:

1\. Protein deficiency / hypoalbuminemia

It was initially believed that a deficiency in the consumption of protein was responsible for the development of kwashiorkor in children.

* Albumin concentrations were also noted to increase steadily within two weeks after refeeding.
* Presence of features similar to congenital nephrotic syndrome, in which the primary pathology is renal loss of albumin.[10]

Multiple evidences have now shown that inadequate intake of dietary protein is not the primary trigger for edematous malnutrition.

* Some patients have edematous malnutrition without hypoalbuminemia.
* Others develop edematous malnutrition (kwashiorkor) despite adequate proportion of protein in the diet (e.g, in exclusively breastfed infants).
* Some recover from edematous malnutrition with supportive care even without enhancing the protein content of the diet.[11][12][13]

2\. Oxidant stress

* Excessive oxidant stress was also proposed as a mechanism of development of kwashiorkor, however, it was discovered that that the administration of antioxidant was not successful in the prevention of the development of this malnutrition in a series of trials.
* Antioxidant depletion is a consequence rather than cause of kwashiorkor.[14]

3\. Microbiome

* Changes in intestinal microbiome have also been suggested as a cause of the development of kwashiorkor.
* This has not been fully supported because evidence shows that neither the fecal microbiota transfer nor the local diet alone was sufficient to cause the malnutrition leading to the conclusion that changes in fecal microbiota are only effects rather than causes of kwashiorkor.[15][16][17]

## Genetics

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Protein-energy malnutrition is frequently reported in Cri du chat syndrome(CDS), a genetic disease that causes developmental delay and global growth retardation.

## Associated conditions

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Some of the conditions that are associated with kwashiorkor include:

* Vitamin A deficiency
* Vitamin D deficiency
* Thiamine deficiency
* Zinc deficiency
* Iodine deficiency
* Iron deficiency
* Dehydration
* Sepsis
* Shigella and Campylobacter infections

## Gross pathology

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Post mortem examination of the liver shows the presence of fatty infiltration and necrosis which disappears with adequate treatment.[18]

## Microscopic pathology

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Both in kwashiorkor and marasmus hair analysis is therefore advocated as a useful diagnostic procedure for both conditions. In both cases, there is a decrease in the amount of melanin present in the scalp hair.

### Kwashiorkor

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* In kwashiorkor, microscopic studies reveal a decreased proportion of hairs in anagen follicles

### Marasmus

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* In marasmic patients, no hairs were in the anagen phase, with a shift to the telogen phase
* Marasmic patients have many more broken hairs when compared with patients with kwashiorkor

## References

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1. ↑ Cederholm T, Jägrén C, Hellström K (1995). "Outcome of protein-energy malnutrition in elderly medical patients". Am J Med. 98 (1): 67–74. doi:10.1016/S0002-9343(99)80082-5. PMID 7825621.CS1 maint: Multiple names: authors list (link)
2. ↑ Lerner AB (1971). "On the etiology of vitiligo and gray hair". Am J Med. 51 (2): 141–7. PMID 5095523.
3. ↑ Saudek CD, Boulter PR, Arky RA (1973). "The natriuretic effect of glucagon and its role in starvation". J. Clin. Endocrinol. Metab. 36 (4): 761–5. doi:10.1210/jcem-36-4-761. PMID 4686383.
4. ↑ Hedeskov CJ, Capito K (1974). "The effect of starvation on insulin secretion and glucose metabolism in mouse pancreatic islets". Biochem. J. 140 (3): 423–33. PMC 1168019. PMID 4155624.
5. ↑ "Wiley: Metabolism at a Glance, 3rd Edition - J. G. Salway".
6. ↑ "Pediatric Research - Mechanisms Behind Decreased Endogenous Glucose Production in Malnourished Children".
7. ↑ Scrimshaw NS, SanGiovanni JP (1997). "Synergism of nutrition, infection, and immunity: an overview". Am. J. Clin. Nutr. 66 (2): 464S–477S. PMID 9250134.
8. ↑ Monk JM, Makinen K, Shrum B, Woodward B (2006). "Blood corticosterone concentration reaches critical illness levels early during acute malnutrition in the weanling mouse". Exp. Biol. Med. (Maywood). 231 (3): 264–8. PMID 16514171.
9. ↑ Auphan N, Didonato JA, Helmberg A, Rosette C, Karin M (1997). "Immunoregulatory genes and immunosuppression by glucocorticoids". Arch. Toxicol. Suppl. 19: 87–95. PMID 9079197.
10. ↑ Coulthard MG (2015). "Oedema in kwashiorkor is caused by hypoalbuminaemia". Paediatr Int Child Health. 35 (2): 83–9. doi:10.1179/2046905514Y.0000000154. PMC 4462841. PMID 25223408.
11. ↑ Golden MH (1998). "Oedematous malnutrition". Br Med Bull. 54 (2): 433–44. PMID 9830208.
12. ↑ Manary MJ, Heikens GT, Golden M (2009). "Kwashiorkor: more hypothesis testing is needed to understand the aetiology of oedema". Malawi Med J. 21 (3): 106–7. PMC 3717490. PMID 20345018.CS1 maint: Multiple names: authors list (link)
13. ↑ Golden MH (2015). "Nutritional and other types of oedema, albumin, complex carbohydrates and the interstitium - a response to Malcolm Coulthard's hypothesis: Oedema in kwashiorkor is caused by hypo-albuminaemia". Paediatr Int Child Health. 35 (2): 90–109. doi:10.1179/2046905515Y.0000000010. PMID 25844980.
14. ↑ Ciliberto H, Ciliberto M, Briend A, Ashorn P, Bier D, Manary M (2005). "Antioxidant supplementation for the prevention of kwashiorkor in Malawian children: randomised, double blind, placebo controlled trial". BMJ. 330 (7500): 1109. doi:10.1136/bmj.38427.404259.8F. PMC 557886. PMID 15851401.CS1 maint: Multiple names: authors list (link)
15. ↑ Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J; et al. (2013). "Gut microbiomes of Malawian twin pairs discordant for kwashiorkor". Science. 339 (6119): 548–54. doi:10.1126/science.1229000. PMC 3667500. PMID 23363771.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
16. ↑ Prentice AM, Nabwera H, Kwambana B, Antonio M, Moore SE (2013). "Microbes and the malnourished child". Sci Transl Med. 5 (180): 180fs11. doi:10.1126/scitranslmed.3006212. PMID 23576812.CS1 maint: Multiple names: authors list (link)
17. ↑ Kau AL, Planer JD, Liu J, Rao S, Yatsunenko T, Trehan I; et al. (2015). "Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy". Sci Transl Med. 7 (276): 276ra24. doi:10.1126/scitranslmed.aaa4877. PMC 4423598. PMID 25717097.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
18. ↑ Lefranc, Violaine; de Luca, Arnaud; Hankard, Régis (2016). "Protein-energy malnutrition is frequent and precocious in children with cri du chat syndrome". American Journal of Medical Genetics Part A. 170 (5): 1358–1362. doi:10.1002/ajmg.a.37597. ISSN 1552-4825.

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