You are on page 1of 7

Nutrition for Disease States

Bier D, et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304

Approach to the Patient and Differential Diagnosis

L. John Hoffer a Bruce R. Bistrian b
Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Que., Canada;
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass., USA

Key Words Introduction

Protein-energy malnutrition · Micronutrient
deficiency · Intestinal malabsorption · Primary care physicians encounter two general
Inflammation · Weight loss · Cachexia · Starvation · kinds of malnutrition, protein-energy malnutri-
Vitamins · Minerals tion (PEM) and micronutrient (vitamin and min-
eral) deficiency.
PEM is the disease that results from chronic
Key Messages
starvation or severe intestinal malabsorption.
• Protein-energy malnutrition (PEM) ordinarily devel-
ops after a period of prolonged inadequate protein
The clinical course of PEM is strongly influenced
and energy consumption. The hallmarks of PEM are by systemic inflammation and coexisting muscle
generalized muscle atrophy and subcutaneous adi- atrophy due to physical inactivity, a primary neu-
pose tissue depletion. romuscular disease, or old age (sarcopenia). By
• Except for cachexia associated with chronic inflam- definition, starving people do not consume (or
matory, end-organ, and malignant diseases, the absorb) enough food, so they are also at risk of
most common cause of weight loss in adults is de-
micronutrient deficiencies.
pression. Chronic diseases, especially of the gastro-
intestinal tract, can negatively affect diet and nutri- With two important exceptions (vitamin D
ent absorption. and iron), overt micronutrient deficiencies are
• Assessment of the severity of PEM and of the extent rare in healthy adults whose body weight is main-
of systemic inflammation is important to determine tained on a conventional diet. The development
when to begin invasive feeding (either by feeding of a vitamin or mineral deficiency in such people
tube or intravenously).
strongly suggests the possibility of a drug-nutri-
• The appearance of a vitamin or mineral deficiency in
a normal adult eating a conventional diet suggests
ent interaction or an as yet undiagnosed disease
the possibility of a drug-nutrient interaction or an of the gastrointestinal system. Conversely, sever-
undiagnosed disease of the gastrointestinal system. al chronic diseases affect diet and can impair nu-
• It is important to identify the cause(s) of a diag- trient absorption. People with these diseases are
nosed micronutrient deficiency in order to adminis- at risk of micronutrient deficiencies, even when
ter the appropriate treatment and to address the their overall food intake is adequate and their
underlying disease. © 2015 S. Karger AG, Basel
body weight is normal. - 12/6/2014 5:47:05 AM
UCSF Library & CKM
Downloaded by:
Table 1. Characteristics of successfully adapted PEM bolic adaptation strongly influences the clinical
course and prognosis of PEM. Survival is com-
Metabolic and endocrine
mon even in prolonged uncomplicated semi-
Secondary amenorrhea starvation, thanks to an adaptive reduction in
Serum free thyroxin and TSH normal resting and total energy expenditure, which, to-
Neurocardiovascular gether with the reduction in the body’s metabol-
Sinus bradycardia ically active tissue mass, lowers energy expendi-
Reduced cardiac output
Hypotension ture enough to match the low rate of energy pro-
Reduced sympathetic tone vision. Metabolic adaptation also increases the
Muscular and functional efficiency of dietary protein assimilation, and
Generalized muscle atrophy and weakness modifies endogenous protein turnover to rees-
Reduced myocardial mass
tablish whole body protein homeostasis despite
Ineffective cough
Reduced ventilatory response to hypoxia the subnormal level of protein consumption.
Drug disposition Successfully adapted PEM is sometimes referred
May be altered [9] to as adult ‘marasmus,’ a term borrowed from pe-
Immune function diatric medicine, and more recently, as ‘starva-
Weakened body barriers due to skin thinning and
ineffective cough
tion-related malnutrition’. The metabolic re-
Reduced febrile response to infection sponse to systemic inflammatory disease, severe
Normal humoral and cellular immunity in the injury or severe infection amplifies body protein
absence of micronutrient deficiencies catabolism and prevents the adaptation to PEM,
Psychological abnormalities
creating a potentially lethal condition. The terms
Anorexia ‘adult kwashiorkor’ and ‘acute disease or injury-
related malnutrition’ are used to describe PEM
that is induced or complicated by intense sys-
temic inflammation. The terms ‘cachexia’ or
There are differences of opinion amongst ex- ‘chronic disease-related malnutrition’ refer to
perts as to the implications of subclinical defi- partially adapted PEM in the context of chronic
ciencies of vitamin D, omega-3 fatty acids, folic mild systemic inflammation, as occurs in in-
acid and cobalamin (vitamin B12) with regard to flammatory polyarthritis, advanced renal, liver,
cancer and cardiovascular disease risk, and age- heart or pulmonary disease, and some cancers.
related cognitive decline. PEM has a worse prognosis in the elderly, largely
because their primary medical or surgical dis-
eases tend to be more serious, and because sarco-
Protein-Energy Malnutrition penia has already reduced their body protein re-
serve [1–5].
Also known also as ‘hunger disease’, PEM PEM and sarcopenia are not uncommon in
typically develops after a period of prolonged in- obese people. The diagnosis will be missed in
adequate protein and energy consumption. The these patients unless the physician specifically
cardinal signs of PEM are generalized muscle at- inquires about changes in food intake and body
rophy and subcutaneous adipose tissue deple- weight, and physically examines their muscles.
tion. The pathologic features of PEM emerge At especially high risk are previously seriously
when the body’s protein reserve, skeletal muscle, obese people who have undergone gastric restric-
has become depleted seriously enough to impair tion surgery, or who have developed a serious
specific physiological functions (table 1). Meta- chronic medical or surgical disease that induces - 12/6/2014 5:47:05 AM
UCSF Library & CKM

88 Hoffer /Bistrian
Downloaded by:

Bier D et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304
Table 2. Adapted and maladapted PEM

Feature Adapted PEM Maladapted PEM

BMI reduced normal or reduced

Muscle mass reduced reduced
Edema usually absent often present
Body weight reduced but stable tissue loss often masked by
extracellular fluid accumulation
Drug disposition may be altered may be altered
Immune function normal impaired
Serum albumin normal reduced
C-reactive protein normal increased
Transthyretin reduced reduced

the cachexia syndrome. In such cases, the loss of and medical evaluation in the large grey zone
muscle outstrips that of fat, and can reach a criti- that lies between adequate nutritional status and
cal degree even in the presence of ample residual clinically important PEM.
adipose tissue. The most useful way to diagnose PEM is in the
classical medical-narrative tradition, which rec-
ognizes PEM as a pathophysiological entity with
Diagnosis and Assessment of Protein-Energy well-defined signs and symptoms, all of which
Malnutrition are strongly modified by the patient’s primary
disease, the presence or absence of systemic in-
Several screening tools are available for identify- flammation, and the presence or absence of other
ing people who have PEM or are at high risk of causes of muscle atrophy (table 2). For example, it
developing it [4]. The simple and well-studied is entirely possible to have a BMI <18.5 but nor-
Malnutrition Universal Screening Tool (MUST) mal health. The MUST will correctly flag such a
categorizes a patient’s risk of ‘malnutrition’ (and person for evaluation, which may disclose a natu-
directs the management response) as low, medi- rally lean phenotype, constant body weight and
um, or high, based on a MUST score of 0, 1 or 2. normal appetite and diet. This person is healthy.
The MUST score is calculated as the sum of points Conversely, severe PEM is entirely possible in a
awarded by considering body mass index (BMI, person whose BMI is 30.
weight/height2): >20, 18.5–20, or <18 (0, 1, or 2
points, respectively), history of involuntary weight
loss: <5%, 5–10%, or >10% (0, 1, or 2 points, re- Importance of Identifying Protein-Energy
spectively), and acute illness or no food intake for Malnutrition and Systemic Inflammation
>5 days (2 points; http://www.scottishintensive- The principal reason for identifying PEM and de-
Tools such as the MUST are valuable in high termining the presence and extent of systemic in-
patient flow situations for they are easy for para- flammation is to determine when invasive feed-
medical staff to use and draw attention to high- ing (either by feeding tube or intravenously) is
risk situations and overt cases of severe PEM. helpful, and when to commence it. Well-adapt-
However, they cannot replace specific diagnosis ed, moderately severe PEM (e.g. BMI approx. - 12/6/2014 5:47:05 AM
UCSF Library & CKM

Approach to the Patient and Differential Diagnosis 89

Downloaded by:

Bier D et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304
17), as often occurs in anorexia nervosa, calls for ease commonly report abdominal bloating, but
careful monitoring and a serious, well-organized they may also be asymptomatic. Coexistent iron,
program to improve the patient’s energy and folic acid, vitamin D or magnesium deficiency in-
protein intake by voluntary means, but it does creases the likelihood of the diagnosis. Some pa-
not represent a medical emergency that requires tients present to their physician with osteomala-
invasive feeding, except when weight loss is con- cia or premature osteoporosis due to chronic vi-
tinuing, electrolyte disturbances occur, and the tamin D malabsorption.
potential for cardiac dysfunction is serious. By Only rarely is an undiagnosed malignancy the
contrast, critically ill patients with severe closed cause of weight loss in the absence of symptoms
head injury, major third-degree body burns, se- or signs that point to serious disease, and espe-
vere sepsis, pancreatitis or multiple injury syn- cially if the complete blood count is normal. Re-
dromes require invasive nutritional support nal cell cancer, painless cancer of the pancreas,
within the first 48 h even if they are well nour- and some types of lung cancer may present with
ished for this therapy can improve their outcome serious constitutional symptoms and weight loss,
by modulating systemic inflammation and miti- but these rare diagnoses can usually be excluded
gating body protein loss. When PEM is absent or by means of a careful physical examination, chest
only mild, and systemic inflammation is only radiograph, urinalysis, and routine blood tests.
moderate (as occurs after uncomplicated major The diagnosis of adrenocortical insufficiency
abdominal surgery, mild systemic infections, and should always be considered when a patient pres-
in chronic inflammatory conditions), invasive ents with weight loss, fatigue, postural hypo-
nutritional support can often be withheld for up tension, and nonspecific gastrointestinal symp-
to one week, as long as the resumption of normal toms [5].
food intake is anticipated in the near future. Pa- Except for cachexia associated with chronic
tients with inflammatory disease and already ex- inflammatory, end-organ, and malignant dis-
isting moderate or severe PEM require earlier in- eases, the commonest cause of weight loss in
tervention [6]. adults is depression. Weight loss and depression
are often exacerbated by social, economic and
mechanical difficulties such as reduced mobility
Evaluation of Involuntary Weight Loss and impaired physical or sensory function,
chewing or swallowing disorders, or ill-fitting
Any patient who reports sustained involuntary dentures. Concurrent thiamine, folic acid, vita-
weight loss requires careful evaluation. The eval- min D or vitamin C deficiency can worsen the
uation should start by measuring body height and mood disturbance of a depressed person and
weight and seeking objective evidence that weight further reduce their food intake in a vicious cy-
loss actually has occurred, and its extent. The cle. People suffering from dementia often dem-
most important question to ask early in the evalu- onstrate a disinclination to eat much food when
ation of such patients is whether their appetite their disease reaches the far-advanced stage. Be-
and overall food intake are normal or decreased. cause they have adapted PEM, these people actu-
Normal appetite and food intake in someone with ally require relatively little food. As long as their
important involuntary weight loss strongly sug- subnormal body weight remains relatively con-
gests the possibility of uncontrolled diabetes mel- stant, there is no medical indication for invasive
litus, hyperthyroidism or malabsorption, and evi- feeding. There is no good evidence that forced
dence to support or refute these diagnoses should feeding improves either the length or quality of
be obtained. Patients with undiagnosed celiac dis- life at this stage of dementia, and some evidence - 12/6/2014 5:47:05 AM
UCSF Library & CKM

90 Hoffer /Bistrian
Downloaded by:

Bier D et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304
Table 3. Important drug- and diet-nutrient interactions

Anticonvulsant drugs increased catabolism of folic acid, vitamin D, and possibly thiamine
Methotrexate impaired folic acid utilization
High-dose loop diuretics increased urinary thiamine excretion
Proton pump inhibitors iron, folic acid and cobalamin malabsorption
Metformin impaired cobalamin absorption
Aminoglycoside antibiotics urinary magnesium wasting
Systemic glucocorticoid therapy blocked vitamin D action
Certain cancer chemotherapeutic agents magnesium, zinc deficiency
Excessive alcohol consumption B vitamin malabsorption, urinary magnesium wasting
Cigarette smoking increased vitamin C catabolism
Excessive consumption of tea, coffee or betel nuts thiamine malabsorption
Grapefruit juice inhibits intestinal CYP3A4, slowing metabolism of many commonly used
drugs including (but not limited to) amiodarone, amlopidine, atorvastatin,
budesonide, buspirone, carbamazepine, cisapride, cyclosporine, felodipine,
lapatinib, lovastatin, nicardipine, nifedipine, nilotinib, simvastatin,
sirolimus, tacrolimus, triazolam, and verapamil [10]
Vegan diet inadequate cobalamin and zinc
Vegetable- and fruit-deficient diet inadequate vitamin C, folic acid and carotenoid
Low-fat diet reduced digestion and absorption of vitamins D and E
Protein-deficient diet inadequate B vitamins and zinc
Seafood-free diet inadequate long-chain omega-3 fatty acids
Sunlight avoidance vitamin D deficiency

that it worsens both of them [7]. On the other due to folic acid or cobalamin (vitamin B12) defi-
hand, simple micronutrient supplementation is ciency. These topics are covered in detail else-
safe and rational in this setting since the para- where in this textbook.
mount consideration at this time is quality of life,
and several micronutrient deficiencies adversely
affect mood. Glossitis

Atrophic glossitis – a reddened tongue that is

Micronutrient Deficiencies smooth in appearance because of atrophy of the
filiform papillae – is a nonspecific inflammatory
The important micronutrient deficiencies are ex- condition that is associated with iron, folic acid,
plained in detail in other chapters in this text- cobalamin, niacin, or riboflavin deficiency.
book. This section provides a short list of practi-
cal tips and an overall diagnostic strategy for eval-
uating vitamin and mineral deficiencies. Drug- and Diet-Nutrient Interactions

Several widely used drugs affect micronutrient

Nutritional Anemias metabolism or excretion and can cause micronu-
trient deficiency. Certain general dietary patterns
The nutritional anemias comprise microcytic are associated with an increased risk of specific
anemia (due to iron, and more rarely copper de- micronutrient deficiencies. Examples of such in-
ficiency) and macrocytic megaloblastic anemia teractions are provided in table 3. - 12/6/2014 5:47:05 AM
UCSF Library & CKM

Approach to the Patient and Differential Diagnosis 91

Downloaded by:

Bier D et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304
When Should a Micronutrient Deficiency Be malabsorb the fat-soluble vitamins (vitamins A,
Investigated or Searched For? D, E and K) even when receiving appropriate
pancreatic enzyme replacement. Patients with
In a classic article, Victor Herbert explained the 5 generalized malabsorption (celiac disease or
possible causes of any micronutrient deficiency: Crohn’s disease involving the small intestine)
inadequate intake, impaired intestinal absorp- malabsorb most micronutrients, especially vita-
tion, impaired metabolic utilization, increased min A, certain B vitamins (including cobala-
excretion or catabolism, and increased metabolic min), magnesium and zinc. Even a mild reduc-
requirement [8]. Herbert’s scheme can be used to tion in the consumption of these micronutrients
formulate two general dictums regarding micro- places these patients at high risk of the corre-
nutrients: sponding deficiency diseases. People who have
Rule 1: When a micronutrient deficiency is di- undergone a subtotal or total gastrectomy (in-
agnosed but only one cause is apparent, search for cluding gastric restriction surgery for obesity)
the second cause. usually require lifelong supplementation with
Rule 2: When a patient has (or is at risk of) two iron, folic acid, and cobalamin. Patients with
independent causes of a micronutrient deficien- chronic or severe inflammatory diarrhea require
cy, it is appropriate to prescribe a suitable supple- zinc supplementation to replace their fecal zinc
ment, test for the pertinent biochemical deficien- losses.
cy, or both.
For example, women with a normal men-
strual cycle and inadequate iron intake are fre- Conclusions
quently iron deficient, but no investigation is
usually required since two causes are apparent. • The hallmarks of PEM are generalized muscle
Iron deficiency in a man or nonmenstruating atrophy and usually, but not always, subcuta-
woman requires a search for the second cause neous adipose tissue depletion.
(gastrointestinal bleeding, parasitic infection, • The severity of PEM, intensity of systemic in-
or celiac disease). A patient with folic acid defi- flammation, and inability to voluntarily meet
ciency and a history of poor diet and chronic nutrient needs determine when artificial nu-
hemolytic anemia (which increases folic acid tritional support is required.
utilization), or poor diet and treatment with • The cause of involuntary weight loss can al-
methotrexate or phenytoin (impaired utiliza- most always be identified from a careful his-
tion and increased catabolism, respectively) tory, physical examination, and routine tests
requires correction of the deficiency but no as explained in this chapter.
further investigation since two causes are ap- • The appearance of a vitamin or mineral defi-
parent. On the other hand, a patient with iso- ciency in a normal adult eating a conventional
lated folic acid deficiency should be evaluated diet requires an explanation. The diagnosis
for a drug-nutrient interaction (including alco- can usually be made using the rules described
hol abuse), malabsorption, or hemolytic ane- in this chapter.
mia. Given the high prevalence of vitamin D • Patients with diseases that increase their risk
deficiency in the general population, any per- of specific vitamin or mineral deficiencies
son prescribed phenytoin requires vitamin D should be assessed with regard to these defi-
supplementation (table 3). ciencies and prescribed preventive supple-
Patients with fat maldigestion (pancreatic in- ments.
sufficiency, biliary cirrhosis, or cystic fibrosis) - 12/6/2014 5:47:05 AM
UCSF Library & CKM

92 Hoffer /Bistrian
Downloaded by:

Bier D et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304
1 Hoffer LJ: Clinical nutrition: protein- 4 Barker LA, Gout BS, Crowe TC: Hospital 7 Hoffer LJ: Tube feeding in advanced
energy malnutrition in the inpatient. malnutrition: prevalence, identification dementia: the metabolic perspective.
CMAJ 2001;165:1345–1349. and impact on patients and the health- BMJ 2006;333:1214–1215.
2 Jensen GL, Mirtallo J, Compher C, et al: care system. Int J Environ Res Public 8 Herbert V: The five possible causes of all
Adult starvation and disease-related Health 2011;8:514–527. nutrient deficiency: illustrated by defi-
malnutrition: a proposal for etiology- 5 Bistrian BR: Nutritional assessment; in ciencies of vitamin B12. Am J Clin Nutr
based diagnosis in the clinical practice Goldman L, Schafer AI (eds): Goldman’s 1973;26:77–86.
setting from the International Consen- Cecil Medicine. Philadelphia, Elsevier 9 Boullata JI: Drug disposition in obesity
sus Guideline Committee. JPEN J Par- Saunders, 2012, pp 1384–1388. and protein-energy malnutrition. Proc
enter Enteral Nutr 2010;34:156–159. 6 Raynaud-Simon A, Revel-Delhom C, Nutr Soc 2010;69:543–550.
3 Macallan D: Infection and malnutrition. Hebuterne X, et al: Clinical practice 10 Seden K, Dickinson L, Khoo S, Back D:
Medicine 2009;37:525–528. guidelines from the French Health High Grapefruit-drug interactions. Drugs
Authority: nutritional support strategy 2010;70:2373–2407.
in protein-energy malnutrition in the
elderly. Clin Nutr 2011;30:312–319. - 12/6/2014 5:47:05 AM

UCSF Library & CKM

Approach to the Patient and Differential Diagnosis 93

Downloaded by:

Bier D et al. (eds): Nutrition for the Primary Care Provider. World Rev Nutr Diet. Basel, Karger, 2015, vol 111, pp 87–93
DOI: 10.1159/000362304