Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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bronchial smooth muscle constriction in the airways

of the lung (bronchospasm) and increased vascular

permeability in the skin, which may be manifested

as swelling or hives and produces itching by affecting

nerve endings. Stimulation of H

receptors in the

stomach results in increased acid secretion, which

can produce indigestion or peptic ulcer disease. The

receptor stimulus–response coupling is presently

unknown. The H

receptors were initially described

in presynaptic nerve endings and on nerve bodies of

histaminergic neurons in the brain, where they func-

tion as autoreceptors to regulate the synthesis and

release of histamine. H

receptors have also been

located in the airways and gastrointestinal tract.

0004 These histamine receptors and their responses can be

antagonized by specific compounds. For the H

recep-

tor, classical antihistamines such as diphenhydramine

and chlorpheniramine act as competitive antagonists

for the receptor. The H

receptor is antagonized by the

compounds, cimetidine and ranitidine, whereas the H

receptor can be antagonized by thioperamide.

Role in Allergic Reactions

0005 Allergic reactions are among the most commonly

recognized effects of histamine. Specific immuno-

globulin E (IgE) antibodies (the class associated with

allergic reactions), which may be directed at various

allergens, including inhalants such as pollens, molds

and animal dander, foods, drugs, or insect venoms,

are bound to the surface of mast cells and basophils

(Figure 2). When the allergen cross-links two IgE

molecules attached to the mast cell or basophil sur-

face, histamine release occurs. Histamine then inter-

acts with tissue histamine receptors (predominantly

), which can produce local reactions such as

sneezing, nasal and ocular pruritus (itching), rhinor-

rhea (nasal discharge), and nasal congestion. In asth-

matics, histamine release may cause cough, wheezing,

and dyspnea (shortage of breath) owing to bronchial

smooth muscle constriction. More generalized sys-

temic symptoms can occur as a result of the ingestion

of foods and drugs, insect stings, or parenteral ad-

ministration of various medications. These reactions,

whether immunological or nonimmunological in

nature, result in a release of histamine leading to a

prompt and sharp rise in plasma histamine levels.

The severity of the reactions is proportional to the

magnitude of this rise. Mild reactions are associated

with low histamine levels, approximately 1 mmol.

Elevation beyond this level can produce generalized

reactions with urticaria (itchy skin rash), gastrointest-

inal disturbance, cardiac arrhythmias, and hypoten-

sion (low blood pressure). At levels in excess of

tbl0001 Table 1 Characteristics of histamine receptor subtypes

receptor H

receptor

Effects of stimulation Bronchial smooth

muscle constriction

Increased gastric

acid secretion

Regulate synthesis and release

of histamine from

histaminergic nervesIncreased vascular

permeability

Increased pepsin secretion

Gut smooth muscle

constriction

Decreased IgE-mediated

basophil histamine

releaseVasodilation Inhibits endogenous norepinephrine

release from sympathetic nerves

Pruritus Increased cyclic adenosine

monophosphate levels

Increased cyclic guanosine

monophosphate levels

Decreased lymphocyte-

mediated cytotoxicity

Stimulus–response

coupling

Linked to phosphoinositide

breakdown

Linked to adenylate cyclase ?

Increased calcium mobilization

Antagonists Chlorpheniramine, diphenhydramine,

loratidine, cetirizine, fexofenadine

Cimetidine, ranitidine,

famotidine, nizatadine

Thioperamide, clobenpropit

Allergen

Mast

cell

Basophil

Histamine

Non immunological

Immunological

IgE-allergen interaction

Complement fragments

, C

)

Cytokines

(histamine-releasing

factors)

Calcium-ionophore

Basic compounds

(48/80)

Opiates

Enzymes (trypsin)

Drugs (radiographic

contrast agents)

Detergents

Physical stimuli (cold)

Chemical

(hyperosmolality)

Hypoxia

fig0002Figure 2 Human mast cell or basophil stimulated to release

preformed histamine by a variety of immunological and non-

immunological mechanisms.

HISTAMINE 3109

12 mmol, life-threatening responses such as severe

hypotension, bronchoconstriction, and ventricular

fibrillation can occur. (See Food Intolerance: Types;

Food Allergies.)

Cardiovascular Effects

0006 Histamine causes vasodilation and increased vascular

permeability. This can result in flushing and decreased

peripheral vascular resistance with subsequent lower-

ing of the blood pressure. Extravasation of fluid results

in angioneurotic edema (swelling of the skin on the

eyes, lips and extremities). These effects are primarily

mediated through H

receptor stimulation. Stimulation

of the H

and H

cardiac receptors can lead to a variety

of rhythm disturbances.

Bronchial Smooth Muscle Effects

0007 Stimulation of the H

receptors in bronchial smooth

muscles causes constriction, producing narrowing of

the airways. This results in breathing difficulties and

wheezing. Stimulation of H

receptors may lead to

relaxation of airway smooth muscle, although this

effect is minimal.

Effect on Gastric Secretion

0008 Gastric mucosal mast cells release histamine, which

causes an increase in gastric acid secretion by gastric

parietal cells through H

receptors. Histamine interacts

with acetylcholaine and gastrin to control acid output

in the stomach. H

receptor antagonists (cimetidine,

ranitidine) are widely used to treat peptic ulcer disease

because of their ability to decrease acid secretion.

Central Nervous System Effects

0009 Two major sources of histamine in the brain are mast

cells and histaminergic neurons. Mast cells are lo-

cated near blood vessels and may affect local blood

flow. Histaminergic neurons (nerve cells whose prin-

cipal neurotransmitter is histamine) are limited in

number, but their axons branch into long ascending

fiber networks that ultimately innervate much of the

brain. Their role is not clear, but the central effects

of histamine include antidiuresis (fluid retention)

through the release of vasopressin, induction of

adrenocorticotrophic-releasing hormone and prolac-

tin secretion, increase in blood pressure and heart

rate, temperature regulation, and control of arousal

mechanisms. The sedative affects of the first gener-

ation antihistamines (e.g., chlorpheniramine, diphen-

hydramine), which block H

receptors functions are

well known. In contrast, second-generation H

blockers (loratidine, fexofenadine, cetirizine) that do

not readily cross the blood–brain are less likely to

induce sedation.

Effect on the Immune System

0010Histamine may have a more general effect on the

immune system than its role in allergic reactions.

Stimulation of H

receptors suppresses lymphocyte

proliferation, T-cell-mediated cytotoxicity, lympho-

kine production, natural killer cell cytotoxicity,

and antibody production by B-lymphocytes. Histamine

in certain dose ranges is chemotactic for eosinophils,

which are the principal effector cells in killing of para-

sites such as schistosomes. Parasites that invade body

tissues generate profound IgE antibody responses.

Interaction of parasite antigens with specific IgE

antibodies on the surface of mast cells causes histamine

release and the subsequent attraction of eosinophils to

the area. Eosinophils can degranulate, releasing their

granular proteins, which are potent toxins to parasitic

organisms. (See Immunology of Food.)

Role of Cellular Proliferation

0011Another physiological role for histamine appears to

be in wound healing, since proliferating tissues syn-

thesize histamine at a higher rate than normal tissue.

The contribution to wound healing is still not com-

pletely understood, however.

Histamine Poisoning

0012Histamine is present in measurable quantities in certain

foods, including cheese, meat, wine, yeast products,

and some vegetables such as spinach and tomatoes

(Table 2). The ingestion of large quantities of histamine

can result in clinical symptoms indistinguishable from

those of an allergic reaction. These include flushing,

throbbing or severe headaches, palpitations of the

heart, abdominal cramps, and diarrhea. Dizziness,

burning of the mouth or throat, nausea, hives, and

angioneurotic edema can occur. Cough, wheezing,

and severe respiratory distress may appear in patients

who have an underlying allergic background, particu-

larly in those with asthma. Symptoms generally begin

30–60 min after ingestion of foods containing high

concentrations of histamine. (See Migraine and Diet.)

Measurement of Histamine in Food

0015A number of analytical methods for measuring the

histamine content of foods have been developed

including fluorometric methods, thin-layer chroma-

tography, oxygen-sensor-based methods, and biologic

methods. In addition, a number of commercially

available enzyme-linked immunoassay test kits are

marketed in the United States and Europe.

3110 HISTAMINE

Scombroid Fish Poisoning

0013 Scombroid fish poisoning results from eating spoiled

fish of the Scombridae and Scomberessocidae fam-

ilies, and produces headache, itching, diarrhea, flush-

ing, and palpatations immediately afer ingestion.

These fishes include tuna, mackerel, skipjack, and

bonito. However, nonscombroid fishes, such as

mahi-mahi, blue fish, amberjack, marlin, herrings,

sardines, and anchovies, have also been implicated in

scombroid-toxin-like illness. Scombroid fish poison-

ing is the most common cause of ichthyotoxicosis

worldwide. In addition to ingestion of fish, histamine

poisoning can occur occasionally through ingestion

of cheese such as Swiss, Cheddar and Gouda. (See

Fish: Spoilage of Seafood.)

001 4 There has been some debate as to whether histamine

is the sole cause of scombroid poisoning, but histamine

is the most likely causative agent of scombroid fish

poisoning. As clinical proof of the role of histamine, a

definitive study involved three patients who were ex-

posedtomarlin,andlaterdevelopedtheclassicalsymp-

toms of scombroid fish poisoning. Urinary excretion of

histamine and its metabolite, N-methylhistamine, was

measured.Urinesamplescollected1–4h afteringestion

of fish show that the histamine and the N-methylhista-

mine levels were respectively nine to 20 times and

15–20 times more than the normal mean, a likely indi-

cation of exposure to high histamine levels. During the

subsequent 24h, the levels fell to four to 15 times and

four to 11 times the normal values, respectively, and

had returned to normal by 14 days. There was no

evidence of mast cell activation as measured by the

principal urinary metabolite of prostaglandin D

.In

addition,ingestionofahighconcentrationofhistamine

has been demonstrated to produce symptoms of scom-

broid poisoning. These symptoms are generally self-

limiting, lasting a few hours, and can be quickly treated

with systemic antihistamine administration. Elevated

histamine levels in fish tissue have been associated with

poor refrigeration, which results in bacterial spoilage

and histamine formation. Bacteria possessing histidine

decarboxylase can contaminate the gastrointestinal

tract, skin, and gills of fish. In the case of cheese, the

entry point to contamination by the histamine-produ-

cingbacteriais raw milk.Refrigerationofraw milk and

fish, good hygiene during food preparation,and careful

control of fermentations will therefore avoid the prob-

lem. Cooking, however, will not destroy histamine.

Seealso: Fish:SpoilageofSeafood; Food Intolerance:

Types;FoodAllergies; Immunology of Food; Migraine

and Diet

Further Reading

Chrush C, Sharma S, Unruh H et al. (1999) Histamine H

receptor blockade improves cardiac function in canine

anaphylaxis. American Journal of Respiratory and

Critical Care Medicine 160: 1142–1149.

Douglas WW (1985) Histamine and S-hydroxytryptamine

(serotonin) and their antagonists. In: Goodman LS and

Gillman AG (eds) The Pharmacological Basis of Thera-

peutics, 7th edn, pp. 605–615. New York: Macmillan.

Helrich K (ed.) (1990) Histamine in seafood: fluorometric

method. In: Official Methods of Analysis of the Associ-

ation of Analytical Chemists,15thedn.Arlington,VA:

Association of Official Analytical Chemists, pp. 876–877.

Lehane L and Olley J (2000) Histamine fish poisoning

revisited. International Journal of Food Microbiology.

58: 1–37.

Marquardt D (1983) Histamine. Clinical Reviews in

Allergy 1: 343–351.

Marrow JD, Marolies GR, Rowland J and Roberts LJ II

(1991) Evidence that histamine is the cause of scom-

broid-fish poisoning. New England Journal of Medicine

324: 716–720.

Pierce FL (1991) Biological effects of histamine: an over-

view. Agents and Actions 33: 4–7.

Price RJ (1999) Compendium of fish and fishery products:

processes, hazards and controls. University of Califor-

nia–Davis. National Seafood HACCP Alliance for

Training and Education. Available at http://www-

seafood.ucdavis.edu

Rafferty P and Holgate ST (1989) Histamine and its antag-

onists in asthma. Journal of Allergy and Clinical Immun-

ology 84: 144–151.

Simon FER (1996) Histamine and H

-receptor Antagonists

in Allergic Disease. New York: Marcel Dekker.

tbl0002 Table 2 Foods with high histamine content

Food Histamine content (mgg

1

)

Fish

Tuna, mackerel, bonito,

mahi-mahi, bluefish

ND–9000

Sardine, herring, anchovy ND–2000

Cheeses

Swiss ND–2500

Roquerfort and blue Trace–4090

Cheddar ND–1080

Gouda Trace–200

Mozzarella ND–50

Wines

American red 0.2–15.5

American white 0.2–11.4

European red ND–30

European white ND–20

Dry sausages Trace–650

Sauerkraut <5.0–200

Soya sauce ND–2740

ND, not detectable.

Modified from Stratton JH, Hutkins RW and Taylor SL (1991) Biogenic

amines in cheese and other fermented foods: a review. Journal of Food

Protection 54: 460–470, with permission, and Diel E, Bayas N, Stibbe A et al.

(1997) Histamine containing food: Establishment of a German Food

Intolerance Databank (NFID). Inflamm Res 46(1): S87–S88.

HISTAMINE 3111

HIV DISEASE AND NUTRITION

C Baldwin, Chelsea and Westminster Hospital,

London, UK

Introduction

0001 The acquired immunodeficiency syndrome (AIDS) is

a disorder characterized by progressive and profound

immunodeficiency that renders the infected individ-

ual highly susceptible to life-threatening opportunis-

tic infections and tumors. It is caused by infection

with the human immunodeficiency virus (HIV). The

first cases of AIDS were reported in June 1981. At the

end of December 1999 the World Health Organiza-

tion reported that there were 47 million cases of HIV

infection worldwide, of which more than 40 000 were

in the UK. AIDS is the now the fourth leading cause

of mortality.

0002 In the early days of HIV infection survival was

limited by the occurrence of lethal opportunistic in-

fections such as Pneumocystis carinii pneumonia and

Mycobacterium avium complex and the lack of anti-

retroviral therapies. As understanding of the natural

history of the disease improved and effective prophy-

laxis against the common opportunistic infections

became available, the associated morbidity and mor-

tality improved. Initial treatment approaches were

limited to the use of nucleoside analog monotherapy,

such as with zidovudine (AZT), which provided only

transient clinical and immunological benefits. Over

1995 and 1996, availability of a new diagnostic test,

viral load measurement, and new drug classes such as

protease inhibitors and nonnucleoside reverse tran-

scriptase inhibitors heralded a new approach to HIV

management. The era of highly active antiretroviral

therapy (HAART), in which suppression of plasma

viral replication to below viral load assay limits (cur-

rently < 50 HIV RNA copies ml

1

) is achieved in a

substantial proportion of individuals, has changed

the clinical management, prognosis, and survival of

people with HIV. The immunologic benefits gained

through virus control with ‘cocktails’ consisting of

three or more drugs have led to dramatic reductions

in the incidence of the major opportunistic infections

and mortality. As the clinical management of HIV

infection has altered, so has its nutritional manage-

ment, although the indications for nutritional support

remain less clearly defined. However, concern that

many therapy combinations or individual compon-

ents of therapy may lead to metabolic perturbations

in individuals with HIV has led to a new era of

nutritional evaluation and investigation in persons

with HIV. This article reviews what is known about

the nutritional status of people with HIV infection,

the nutritional problems specific to this infection

and its treatments, and the objectives of nutritional

support.

Nutritional Status of People with HIV

Infection

0003Before the introduction of HAART, profound weight

loss and wasting were amongst the most common

observations in people with HIV infection. In 1987

the Centers for Disease Control (CDC) included

HIV wasting (> 10% loss of baseline body weight þ

pathogen-negative diarrhea or persistent night

sweats), which could not be explained by the presence

of concurrent infection, in the list of AIDS-defining

illnesses. Two-thirds of men with AIDS were reported

to weigh less than 90% of their usual body weight.

Since 1995 effective combination therapy has been

associated with significant weight gain in the majority

of people. Indeed, some patients report gaining exces-

sive amounts of weight on therapy. This may be due

to a modest reduction in resting energy expenditure

(REE) and improvement in gut function and nutrient

absorption, and additionally, the resolution or pre-

vention of minor infections which may contribute to

bouts of weight loss. Weight loss and wasting are less

common in people receiving HAART but still occur

in some people who have an excellent antiviral/

immunological response, in some cases as a result of

side-effects of therapy. Additionally, not all patients

respond or respond durably to HAART.

0004Weight loss in HIV infection is often multifactorial

in its causation, even within individual patients. The

management of weight loss is dependent on an under-

standing of the underlying pathophysiology.

0005Two major mechanisms dominate the pattern of

tissue loss in HIV-related weight loss:

0006Protein-energy malnutrition (PEM) is a condition

synonymous with starvation, resulting when the

body’s needs for protein, energy, or both cannot be

met by diet. In HIV infection this could result from

inadequate intake or nutrient malabsorption.

0007Cachexia is a clinical syndrome characterized by

a mixture of metabolic abnormalities that lead

to weight loss through accelerated wasting of

host tissue mass, and failure of adequate nutrient

intake, absorption, and utilization. This is

3112 HIV DISEASE AND NUTRITION

different from malnutrition in that there is a

marked and rapid depletion of muscle rather

than fat.

The major difference between PEM and cachexia is

that the nutritional effects ofstarvation can be reversed

by the provision of appropriate feeding whilst the

nutritional changes associated with cachexia cannot.

0008 Malnutrition is associated with important clinical

consequences independent of the underlying disease.

Chronic undernutrition leads to deficiencies in work

capacity, immune function, wound healing, organ

function, mental state, and growth in children. When

secondary malnutrition occurs as a result of disease it

is associated with additional problems: reduced qual-

ity of life, disease complications, poor clinical out-

comes, and increased costs of management. In a study

of men with AIDS wasting (mean weight loss 15%),

the extent of muscle wasting was highly predictive

of the strength and functional capacity of the leg

muscles, demonstrating the important relationship

between loss of lean body mass and functional

capacity. Additionally, in people with HIV infection,

weight loss has profound prognostic implications,

predicting shortened survival, increased risk of hospi-

talization, and increased risk of being diagnosed with

an opportunistic infection. The effects of weight loss

are independent of immune function (as measured by

CD4 lymphocyte counts). Recently published obser-

vations have quantified the impact of weight loss in

HIV infection, demonstrating that a weight loss trend

over a 4-month period of even as little as 0–3% was

predictive of increased subsequent mortality. Weight

loss of more than 5% was associated with a relative

risk of 1.88 (P < 0.001) of developing an opportunis-

tic infection in the follow-up period.

Characteristics of Malnutrition

0009 Early studies of weight loss and body composition

conducted in a group of men with AIDS-related

weight loss, compared with an HIV-negative control

group, demonstrated that weight loss in this group

was associated with a profound depletion of body cell

mass that was greater than that expected for the body

weight reduction, whereas fat mass was largely pre-

served. These studies were performed before the first

antiretroviral drugs became available and therefore

represent untreated HIV infection.

0010 A 1993 study examined patterns of weight change

in 30 individuals with HIV over a period of 9–49

months. Two typical patterns of weight change were

described – acute and chronic weight loss. Acute

weight loss (Figure 1) was usually rapid, occurring

at a rate of 4 kg per month or greater, and was

associated with opportunistic infections, mainly

nongastrointestinal. Recovery to usual or preillness

weight was common. Chronic weight loss (Figure 2),

in contrast, occurred at a slower rate of less than 4 kg

per month, was progressive, and was associated

mainly with gastrointestinal disease. These observa-

tions have a number of important implications for the

nutritional management of people with HIV. First,

they demonstrated that HIV infection was not associ-

ated with unremitting weight loss. Treatment of the

underlying infection leads to the ability to regain

weight, often back to preillness weight, and therefore

HIV does not prevent an appropriate anabolic re-

sponse. Second, weight loss may precede specific

signs and symptoms of infection and, therefore, is of

significant diagnostic value. This potential diagnostic

role prompted the recommendation that weight

200 400 600 800

Weight (kg)

fig0001Figure 1 Example of acute weight loss episodes (time 0 ¼stage

IV diagnosis). Reproduced with permission from; Macallan DC,

Noble C, Baldwin C et al. (1993) Prospective analysis of patterns

of weight change in stage IV human immunodeficiency virus

infection. AmericanJournalofClinicalNutrition 58: 417–424.

0 200 400 600 800

Weight (kg)

Days

fig0002Figure 2 Example of chronic weight loss (time 0 ¼ stage IV

diagnosis). Reproduced with permission from; Macallan DC,

Noble C, Baldwin C et al. (1993) Prospective analysis of patterns

of weight change in stage IV human immunodeficiency virus

infection. AmericanJournalofClinicalNutrition 58: 417–424.

HIV DISEASE AND NUTRITION 3113

change be recorded in all patients and be represented

graphically in patient notes. Third, weight gain

achieved following recovery from weight loss epi-

sodes usually occurs without the use of invasive nu-

tritional support and, therefore, could be seen to

represent the natural history of weight change in

HIV infection.

Body Composition and Effective Antiviral Therapy

0011 Advances in the management of HIV infection have

had a significant impact on the incidence of weight

loss and wasting but nutritional status has not

returned to normal. In 1998 the first reports appeared

of altered body composition in people with HIV in-

fection. A syndrome of fat redistribution and associ-

ated metabolic abnormalities has been described

which has become known as lipodystrophy. The syn-

drome(s) consists of accumulations of fat (lipohyper-

trophy) in the abdominal area (intraabdominal in

men, breast enlargement in women), posterior neck

(‘buffalo hump’), and fat loss (lipoatrophy) in the face

(particularly the temporalis, nasolabial, and buccal

fat pad), arms and legs (leading to vein prominence).

Metabolic changes, including hypercholesterolemia,

hypertriglyceridemia, hyperglycemia, and insulin

resistance, are also reported in association with the

syndrome. There is so far no accepted definition for

the syndrome of fat redistribution or any accepted

set of standardized diagnostic criteria. However, the

clinical presentation is characteristic and highly stig-

matizing. Reports of the prevalence of the fat redistri-

bution syndrome vary widely, depending in part on

definition, from as low as 2% up to 84%. Initially the

syndrome was thought to be associated solely with

protease inhibitors, but more recently it has been

reported in people receiving all classes of antiretro-

viral therapy. Several authors have proposed mechan-

isms to explain the development of the syndrome but

the causes remain unknown. Identified risk factors

include duration of antiretroviral therapy, older age,

and white race. The use of protease inhibitors may

accelerate time to syndrome onset.

0012 An accurate assessment of body composition in

people with fat redistribution is difficult. Bioelectric

impedance analysis will not accurately measure body

composition in this syndrome as it is unable to detect

regional distribution or assess any changes that may

occur. Dual X-ray absorptiometry (DEXA) scanning

can determine regional fat compartments and may be

useful in assessing people with fat redistribution, al-

though the absence of data on normal body compos-

ition as well as regional body composition may limit

its usefulness in diagnosing the syndrome. Computer-

assisted tomography and magnetic resonance imaging

can quantify body fat and therefore may be of most

use in assessing body composition in this syndrome,

although they are not always practical.

Deficiencies of Individual Nutrients

0013A number of studies have attempted to measure vita-

min and mineral levels in HIV-positive subjects com-

pared with a control group. Overall, results suggest

that specific nutrient deficiencies are common in HIV

infection and especially in the advanced stages of

disease. The actual extent of overt and marginal defi-

ciency and their significance is unclear. More infor-

mation is needed on factors that might influence

nutrient status measures, such as nutrient intake,

drug–nutrient interactions, the influence of disease,

and the presence or absence of infection; improve-

ments in methods of nutrient assessment are also

needed.

0014There is extensive literature on the relationship of

nutrient deficiencies to immune function. Nutritional

deficiencies can impair immunity and so influence a

person’s susceptibility to infections. It has been sug-

gested that dietary manipulations might diminish or

reverse the immune defects caused by HIV infection

and enhance resistance to opportunistic infections. At

present there is insufficient evidence to support the

use of particular nutrient supplements to modulate

immune function. The use of vitamin and mineral

supplements containing 100% of the recommended

daily allowance for all micronutrients has been pro-

posed in the USA by the Task Force on Nutrition

Support in AIDS to insure sufficiency. Although

some authors have suggested supplementary levels

of some vitamins and minerals in people with HIV

in an attempt to achieve normal plasma levels, the

benefits of this approach in the short and long term

are unclear.

0015There is no evidence that megadoses of any vitamin

or mineral will alter the course of disease or improve

the nutritional status of people with HIV.

The Mechanisms of Malnutrition in HIV

Infection

0016There are a number of factors that may lead to the

development of malnutrition in HIV infection: altered

food intake, malabsorption of nutrients, and changes

in metabolism.

Reduced Food Intake

0017Food intake in an HIV-positive person may be

affected by many physical and emotional factors.

Anorexia is an accepted response to infection. Loss

of appetite is a problem in people with HIV infection

and may result from the associated opportunistic

3114 HIV DISEASE AND NUTRITION

infections, malignancies, gastrointestinal symptoms,

side-effects of medication, emotional issues, or a com-

bination of these.

Nutrient Malabsorption

0018 Malabsorption is common in HIV infection and may

result from intestinal pathogens and the side-effects

of medication.

Metabolic Alterations

0019 Hypermetabolism in association with febrile illness

is a familiar concept. A number of investigators

have measured REE in asymptomatic HIV infection

and demonstrated an increase of around 10%. The

presence of opportunistic infections is associated

with greater increases in REE of up to 34%. There

is still much to be learned about the mechanisms of

metabolic regulation that accompany weight loss

and wasting in HIV. It is not understood why an

increase in metabolic rate is not accompanied by an

increase in food intake. Cytokines such as tumor

necrosis factor (TNF) and interferons are respon-

sible for many aspects but there is now evidence

that they are not alone responsible for the wasting

process.

0020 If a person is to be in energy balance, then energy

intake must be equal to REE plus energy used in

activity (total energy expenditure (TEE)). A study

published in 1995 examined the relative contribu-

tions of changes in energy expenditure and intake to

the pathogenesis of HIV-related weight loss and has

provided important information on the underlying

causes of weight loss in HIV infection. It examined

energy balance in a group of 21 HIV-infected individ-

uals. TEE, REE, activity levels, and food intake were

measured during episodes of weight loss, weight gain,

and during periods of weight stability. It confirmed

that REE is raised in individuals with HIV infection

and that during periods of opportunistic infection

REE is elevated even further. During periods of

weight loss TEE was not elevated but reduced to be

almost equal to REE, accounted for by a reduction

in activity levels, and was raised during periods of

weight gain, therefore TEE could not account for the

changes in energy balance necessary to cause weight

changes. Measurement of energy intake confirmed

that reduced energy intake is the prime determinant

of weight change in HIV-associated weight loss. It has

been suggested that it is possible to predict the com-

position of tissue loss during periods of starvation

and that there is an inverse relationship between the

amount of body fat and the ratio of fat-free mass

(FFM) to total tissue lost during food restriction. In

the study mentioned above, the amount of FFM lost

during periods of weight loss was 58% of the total,

which is similar to that predicted using Forbes’ equa-

tion and is consistent with undernutrition as the

underlying mechanism of weight loss in this group

of people with HIV.

0021These findings suggest that an adequate supply of

nutrients could prevent weight loss or promote weight

gain in people with HIV-related weight loss but

simple deficiency of nutrients is not the only possible

cause of weight loss. Several other aspects of altered

metabolism have been described in people with HIV

infection, termed metabolic dysregulation, which

may account for relatively greater losses of lean

body mass relative to fat in some people (a predomin-

antly cachectic mechanism). First, reduced de novo

lipogenesis is a classic response to starvation in

healthy subjects. In AIDS wasting, de novo lipogen-

esis is increased in the majority of subjects. Second,

AIDS wasting is associated with hypertriglyceridemia

and low serum cholesterol levels compared with HIV-

negative controls, which may be indicative of futile

cycling of free fatty acids and triacylglycerols. Futile

cycling is thought to be mediated by TNF and is said

to occur when free fatty acids are released from fat

and returned to the liver, where they are reesterified in

triacylglycerols and secreted as very-low-density lipo-

proteins (VLDL), to return to the fat cell for break-

down and restorage as triacylglycerols. Third, AIDS

wasting is associated with serum testosterone levels in

the lowest quartile of the normal range. Low testos-

terone concentrations are observed in about 50% of

men with wasting and are usually associated with

advanced disease, weight loss, and hypogonadism,

suggesting that the low concentrations are stress- or

starvation-induced.

0022The above aspects of metabolic dysregulation do

not occur uniformly amongst people with HIV-

related weight loss and considerable heterogeneity

has been noted in this population. It has been sug-

gested that people with AIDS wasting fall into differ-

ent pathogenetic subsets and that it may be possible

to categorize people into those who have lost weight

as a result of ‘starvation’ and who may therefore

respond to provision of nutrients and differentiate

them from the subset of patients who are cachectic

and may not be able to respond appropriately to

nutrition.

Nutritional Problems for People with HIV

0023People who are HIV-positive are vulnerable to a wide

range of pathogens. A person’s ability to continue to

eat normally may be altered by the disease itself or by

the treatment (Table 1). The nutritional problems for

people with HIV fall into three main categories:

HIV DISEASE AND NUTRITION 3115

1.0024 Wasting and weight loss resulting from symptoms

that have an impact on food intake, such as dys-

phagia, taste changes, pain, nausea and vomiting,

and shortness of breath

0025 Restrictions on food intake imposed by antiretro-

viral treatments

0026 The side-effects of antiretroviral therapy, such as

nausea, vomiting and diarrhea and dsylipidemias,

impaired glucose tolerance, and body shape

changes

Dietetic management can be effective in managing

weight loss resulting from a range of symptoms.

Drug regimens may demand one of the following

adaptations:

0027 Eating at the same time as taking the drug

0028 Avoiding food for an hour or two after taking the

drug

0029 Eating or avoiding certain types of food in order to

insure maximum absorption of medication

Dietary advice to accommodate antiretroviral ther-

apy is highly individualized and tailored to specific

circumstances and to specific combinations of drugs

and therefore will not be covered in any detail here.

0030The metabolic and body shape changes associated

with HIV represent a new challenge in the manage-

ment of HIV infection. The aim of the management of

fat redistribution is to replace lost fat and to reduce

accumulated fat deposits. So far, management has

tended to concentrate on changes to drug therapy

which involve switching away from drugs implicated

in the causation of the syndrome. A range of interven-

tions have been tried and modest benefits have been

reported, which may in part relate to the relaxation of

dietary restrictions associated with some medications

and to improved well-being. The use of recombinant

human growth hormone has been shown to have

some positive benefits, predominantly on reducing

accumulations of abdominal and dorsocervical fat,

in a few small studies. Diet and exercise remain

unevaluated as possible management strategies for

the fat redistribution syndrome.

0031The clinical significance of the metabolic compli-

cations associated with the fat redistribution syn-

drome are not known. A small number of reports

tbl0001 Table 1 Common manifestations of acquired immunodeficiency syndrome (AIDS) and potential nutritional problems

AIDS-relatedinfections andcancers Potentialnutritional problems

Opportunistic infections

Fungal

Candida

Oral Sore mouth, altered taste perception, anorexia, reduced saliva production

Esophageal Dysphagia

Cryptococcus

Meningitis Pyrexia, nausea, and vomiting

Protozoan

Toxoplasmosis Pyrexia, ethargy, confusion

Pneumocystis carinii pneumonia (PCP) Pyrexia, dyspnea, anorexia and weight loss, tiredness and lethargy

Bacterial

Mycobacterium avium intracellulare (MAI) Pyrexia, anorexia and weight loss, diarrhea and malabsorption

Viral

Cytomegalovirus (CMV) Pyrexia, diarrhea, and malabsorption

Herpes simplex (oral) Dysphagia

Human immunodeficiency virus (HIV) Pyrexia, diarrhea, and weight loss

Parasitic

Cryptosporidium Diarrhea and malabsorption, anorexia, weight loss, nausea and vomiting, pyrexia

Microsporidia

Cyclospora

Isospora

Cancers

Kaposi’s sarcoma (gastrointestinal) Dysphagia, sore mouth, anorexia, abdominal discomfort and obstruction, diarrhea, and

malabsorption

Non-Hodgkin’s lymphoma Anorexia, weight loss, dysphagia, diarrhea

Other

AIDS enteropathy Diarrhea and malabsorption, weight loss

AIDS encephalitis Confusion, dementia, lethargy

Side-effects of HAART Nausea, diarrhea, dyslipidemias

Coinfections e.g. hepatitis B and C, alcoholic liver disease

HAART, highly active antiretroviral therapy.

3116 HIV DISEASE AND NUTRITION

have been published of myocardial infarction in

people on HAART. Additionally, fatal pancreatitis

with hypertriglyceridemia has been reported. The

extent to which lipid disturbances and hyperglycemia

are associated with an increased risk of vascular

disease and increased survival is unknown and is the

subject of a 15 000-patient global study. Results are

not expected for another 2 years. Currently, manage-

ment of isolated hyperlipidemia is through conven-

tional dietary advice and lipid-lowering agents. As

some statins (human menopausal gonadotropin

coreductase inhibitors) may interact with protease

inhibitors, advice should be sought before introdu-

cing these agents.

0032 The effective treatment of the fat redistribution

syndrome will be most successful only once the mech-

anisms are understood. However, approaches which

in small, mostly cohort studies have yielded benefit in

some patients include exercise, growth hormone,

antiretroviral therapy modification, and metformin.

No uniformly effective management has been estab-

lished. The use of supplements such as acetyl-l-carni-

tine, coenzyme Q-10 (ubiquinone), and riboflavin to

support mitochondrial function in adipocytes has

been widely suggested but not evaluated.

Objectives of Nutritional Support

0033 The objectives of nutritional support in people with

HIV infection vary widely depending on the stage of

the disease and the presence or absence of symptoms

which have an impact on nutritional intake.

Asymptomatic HIV Infection

0034 When a person is diagnosed with HIV infection but

is symptom-free, he or she often considers dietary

change within a framework of lifestyle changes to

maintain health. Dietary information is available in

a variety of media, from the advice of friends and

family, to magazine articles, television programs, and

the internet. The rationale for making dietary changes

in people with asymptomatic infection is based on

avoiding nutrient deficiencies, which may have an

impact on immune function and maintaining an

ideal body weight. Advice is aimed at promoting a

regular balanced intake of a variety of foods. There is

no evidence for increased or decreased requirements

of any nutrient compared with the HIV-negative

population.

0035 Prior to the introduction of HAART, healthy-

eating guidelines designed to promote a reduced

intake of fat and sugar and an increase in fiber were

considered inappropriate in people with HIV. Since

the introduction of HAART and the associated

survival advantages and potential cardiovascular

side-effects, it may be pertinent to provide dietary

advice in line with healthy-eating guidelines. There

is no evidence base for such a recommendation,

however.

0036People with HIV infection are at greater risk of

contracting food- and waterborne infections since

they are immunosuppressed and often suffer from

coexisting disease or infections. It is generally recom-

mended that people with HIV are given advice on

food hygiene and water safety. Some local policies

specify that this happens once a defined level of

immunosuppression is reached. Cryptosporidiosis is

a waterborne protozoa which can cause chronic diar-

rhea in immunosuppressed individuals. There have

been reports of outbreaks of cryptosporidial infection

in people with HIV infection where tap water has

been implicated as the cause. The UK Department of

Health recommends that people with HIV with a low

CD4 lymphocyte count should boil all water (includ-

ing still, bottled water) used for drinking, brushing

teeth, and washing fruit and salad vegetables. This

practice has not been adopted throughout the UK and

will vary with local policies.

0037Unproven diet therapies There is currently no cure

for HIV/AIDS. Faced with this, many people seek to

take control of their own treatment and this often

involves the use of diet therapies, which claim to

prevent the progression of the disease, or to cure it.

There can be tremendous psychological benefit from

following a particular treatment, and people should

not be discouraged from following a regime of their

choice, but helped to evaluate and adjust their eating

habits in order to meet nutritional goals. It is import-

ant that eating remains an enjoyable experience and

that people do not subject their food choice to

unnecessarily rigid rules that may detract from

enjoyment.

0038The following considerations are helpful in evalu-

ating dietary options:

0039The diet should not contain substances in amounts

that may be physically harmful.

0040It should not completely replace health care that is

generally accepted as effective.

0041It should allow for an adequate energy and protein

intake along with a variety of foods.

0042It should not incur unnecessary expense or hard-

ship.

Symptomatic HIV Infection

0043Many of the manifestations of HIV infection affect a

person’s ability to eat normally and maintain body

weight, and therefore nutritional support is indicated.

HIV DISEASE AND NUTRITION 3117

The management of a person with weight loss should

involve a number of steps: first, diagnosis and treat-

ment of any underlying opportunistic infections,

second, control of any symptoms that may have an

impact on food intake; and third, dietary advice.

0044 In the first instance dietary advice should be to

maximize food intake by making alterations in the

type and timing of meals, including well-chosen

snacks between meals, and possibly modifying exist-

ing foods to increase their energy and protein content.

This approach is a basic tool of dietetics that has

received little research attention. A small uncon-

trolled study in 34 people with HIV demonstrated

that dietary advice was associated with significant

improvements in nutrient intake, weight, and anthro-

pometric indices. A recent randomized controlled

study of dietary counseling with or without oral nu-

tritional supplements showed that nutritional coun-

seling can achieve a substantial increase in nutrient

intake in 50% of malnourished people with HIV

which after 6 weeks was not associated with changes

in weight and nutritional status.

0045 A second line of dietary intervention is the use of

specialized proprietary food supplements in combin-

ation with a balanced food intake. These usually take

the form of prepacked drinks that are nutrient-dense

and nutritionally complete. Since the appearance of

these products 12–15 years ago, they have acquired

the reputation of being able to promote weight gain in

a person who is losing weight. A systematic review of

energy-dense supplements in illness-related malnutri-

tion has demonstrated significant benefits to weight

and nutritional status but the effects on morbidity

and mortality are less clear. A small number of studies

have looked at the use of oral nutritional supplements

in people with HIV and demonstrated short-term

benefits to nutritional intake, weight, and nutritional

status. More studies are needed to clarify the role of

nutritional intervention in HIV-related weight loss

and particularly the effects on morbidity, mortality,

and clinical outcome.

0046 If adequate nutrition cannot be achieved orally,

then enteral or parenteral nutrition should be con-

sidered. The major indication for nutritional support

in HIV is the failure to maintain body weight. The

main goals of nutritional support are to improve

survival morbidity by reducing the complication rate

associated with secondary infections and to improve

quality of life. There are a small number of studies

that have looked at the efficacy of nutritional support

in HIV. In general they have concentrated on the

safety and on the ability to replenish lean body

mass. Reports of rates of infection vary considerably

with enteral and parenteral feeding but the general

conclusions are that nutritional support can be

provided with safety in people with HIV infection

but should be undertaken with caution because of

the serious risk of infection. A small number of

studies have looked at the ability to replenish lean

body mass using enteral and parenteral nutrition.

The results suggest that nutritional support can effect-

ively maintain body composition and reverse the

depletion of fat and lean tissue in patients with weight

loss in the absence of concurrent infection or when

provided in conjunction with effective treatment of

an infection. In the stressed catabolic patient with

systemic infection, malnutrition is not restored

towards normal with nutritional support and weight

gains tend to be mainly fat and not lean body mass. It

is important to note that in some studies the provision

of artificial feeding led to prolonged survival with

improved functional capacity and resumption of

employment – benefits which should not be over-

looked when considering the initiation of nutritional

support.

0047The provision of nutritional support in the terminal

stages of disease is a controversial issue. One study

demonstrated benefits to quality of life associated

with the provision of parenteral feeding in the ter-

minal stages of illness. Recently, studies of the effects

on survival of enteral and parenteral feeding have

underscored the importance of starting feeding before

it is too late.

0048The area currently receiving the most interest in

relation to nutrition and HIV infection is the use of

growth hormone and anabolic steroids for their

ability to replenish lean body mass. Testosterone

and testosterone analogs and recombinant human

growth hormone have been demonstrated to replen-

ish lean body mass effectively in people with 5–15%

weight loss. Benefits have been demonstrated with

and without supervised exercise programs. This is a

relatively new area of nutrition and the potential role

of anabolic therapies in conjunction with the provi-

sion of nutritional support raises many questions:

0049Does increasing lean body mass change the prog-

nosis?

0050Is long-term anabolic steroid use safe?

0051Which patients are likely to benefit – those with

mild or advanced disease?

0052Should steroids be used intermittently or continu-

ously?

0053Which anabolic drug is most effective?

Advances in the understanding of the pathophysiol-

ogy of weight loss wasting have led to a greater

understanding of the role of nutrition in HIV infec-

tion. The primary determinant of weight loss is fre-

quently reduced food intake but this cannot alone

explain all aspects of HIV-associated wasting and

3118 HIV DISEASE AND NUTRITION