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

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listeriosis cases have been shown to be caused by

serotypes 1/2a, 1/2b, and 4b. Further analyses has

revealed that serotype 4b is prevalent in many Euro-

pean countries. In North America, serotypes 1/2a

(Canada) and 4b (USA) are most often recovered in

cases of listeriosis. Again, the reason for the differ-

ences observed in serotype and geographical distribu-

tion is unclear. Equally, it is not known at present why

only three serotypes cause most of the illness.

Food and Clinical Diagnosis

0007 The food microbiologist has the task of analyzing a

food product for the presence of L. monocytogenes.

They must be able to achieve this goal as rapidly as

possible, as the food implicated may have already

been consumed prior to the identification protocol

being completed. Because listeriae are found through-

out nature and in a wide variety of foods, there is

no universal protocol at the moment. The majority of

identification methods for the detection and enumer-

ation of L. monocytogenes are cultural in nature.

Other methods include the use of DNA probes, amp-

lification-based methods, antibody-based technolo-

gies, and other rapid methods.

0008 In Canada, the Bureau of Microbial Hazards

(part of the Health Products and Food Branch)

uses a detection method developed for all food

and environmental samples (Figure 1). Presumptive

colonies are then subjected to biochemical testing,

using the criteria listed in Table 2 to differentiate

L. monocytogenes from other species. Enumeration

would involve macerating the sample with peptone

water and plating on to any of two LPM, Oxford,

MOX, or Palcam agar plates, followed by incubation

at 30



C (LPM) or 35



C (Oxford, MOX, Palcam).

0009The cultural method utilizes selective agents with

the hope of allowing cells of L. monocytogenes to

grow and competing flora to be inhibited. LEB, also

known as University of Vermont broth, contains

nalidixic acid and acriflavin as selective agents.

LPM medium contains the Gram-positive and

Gram-negative inhibitory compounds, lithium chlor-

ide, phenylethanol, and moxalactam. Fraser broth

contains lithium chloride, nalidixic acid, and acrifla-

vin. The addition of esculin and ferric ammonium

citrate causes a darkening of the broth or agar in the

presence of Listeria species (Listeria species have the

ability to hydrolyze esculin, and hydrolysis of esculin

turns the medium black, denoting a presumptive posi-

tive test). Oxford agar contains lithium chloride,

cycloheximide, colistin, acriflavin, fosfomycin, and

cefotetan as selective agents, in addition to esculin

and ferric ammonium citrate. Palcam agar and broth

contain, in addition to esculin and ferric ammonium

citrate, lithium chloride, polymixin-B-sulfate, ceftazi-

dime, and acriflavin. Interestingly, it would appear

that Palcam is preferred in Europe, while LPM,

Oxford, and modified Oxford are used predomin-

antly in North America. Many laboratories across

the world are currently working on novel formula-

tions that one day may be superior to currently used

media.

0010Other methods have been reported in the literature

for the detection and enumeration of L. monocyto-

genes in foods. The first report of a monoclonal anti-

body specific for the genus Listeria was reported in

1987. Since then, antibody-based detection methods

have been described. These are based on the enzyme-

linked immunosorbent assay. Many companies offer

commercially available kits that use the antibody–

antigen–antibody sandwich technique as the basis

for detection. Antibodies have also been used in con-

junction with magnetic beads. The beads are covered

with Listeria-specific antibodies and mixed with the

sample to be tested. A magnetic field is applied to

separate the magnetic beads on which the Listeria

cells are bound. After a washing step, other methods

(for example, cultural methods) may be applied.

Monoclonal antibodies have been used to serotype

the genus Listeria, supplemented by hemolysis of

blood and in vivo mouse assays (Table 3).

0011There are many protocols described that have, as

their basis, hybridization of genetic material (DNA).

Many probes have been described and used in colony

hybridization methods, as have polymerase chain

Blend or stomach sample in LEB broth and

incubate at 30 C for 48 hours.

Confirmation tests on presumptive isolates.

Tests include Gram-stain, catalase,

hemolysis, motility,

mannitol/rhamnose/xylose acid production,

CAMP test, serology, biochemical or rapid

identification kits.

Streak positive modified Fraser broths onto

selective agar plates. Reincubate negative

Fraser broths for an additional 24 hours.

Incubate the agar plates for 24 to 48

hours.

At 24 and 48 hours, transfer 0.1 ml of LEB

into modified Fraser broth. Incubate 24 to

48 hours at 35 C. (Optional: streak LEB

onto plates).

fig0001 Figure 1 Flow chart for the isolation of L. monocytogenes from

environmental and food samples.

LISTERIA

/Listeriosis 3583

reaction protocols. These methods offer the advan-

tage of reducing the time required to obtain a positive

results. However, a possible disadvantage of these

methods is that isolation of L. monocytogenes is not

required. A consequence of this would be the lack of

pure isolates to do molecular typing and build on

currently existing databases. Some of the existing

alternative methods are summarized in Table 4.

0012In the clinical setting, the diagnosis of listeriosis is

dependent on the isolation of the organism from nor-

mally sterile sites. These include the blood, placenta,

amniotic, or cerebrospinal fluid (CSF). A positive

diagnosis may also be ascertained through analysis

of stool samples. Samples obtained from normally

sterile environments are streaked on to blood agar.

On sheep blood agar, narrow zones of b-hemolysis

tbl0002 Table 2 Characteristics differentiating the species of the genus Listeria

Characteristics L. monocytogenes L. innocua L. seeligeri L. welshimeri L. ivanovii L. gravi L. murrayi

Gram stain

þþ þ þþþ

b-hemolysis

þ  þ



Mannitol (acid production)

þþ

L-Rhamnose (acid production)

þ d  d d

D-Xylose (acid production)

þþþ

CAMP test (S. aureus)

þ  

CAMP test (R. equi) þ

Acid production from:

L-Arabinose 

Dextrin d þþ

Galactose d  d þþ

Glycogen 

Lactose d þþþþ

D-Lyxose  þþ

Melezitose d d d 

Melibiose 

a-Methyl-

D-glucoside þþ þþþ

a-Methyl-

D-mannoside þþ

þ

Sorbitol d 

Soluble starch  þþ

Sucrose  dd

Voges–Proskauer þþþþþþþ

Hydrolysis of:

Cellulose 

Hippurate þþ þ

Starch d d 

Lecithinase d d þ

Phosphatase þþþþþþþ

to NO

reduction  þ

Pathogenicity for mice þþ

Tests most often used in differentiating the listeriae.

Standard symbols: þ , positive; , negative; þ, > or equal to 90% positive; , > or equal to 90% negative; d, 11–89% of strains are positive.

Not all strains of L. monocytogenes exhibit b-hemolysis – the type strain ATCC 15313 is a nonhemolytic mutant on horse, sheep, and bovine blood.

A very wide zone or multiple zones of hemolysis are usually exhibited by L.ivanoviistrains.

Of 30 strains, ATCC 15313, the type strain, did not give a positive reaction.

Of 10 strains tested, one gave a positive reaction.

tbl0003 Table 3 Serology, hemolytic activity, and mouse virulence for Listeria species

Species Serotype Hemolysis of 7%

horse blood agar

Mouse virulence

L. monocytogenes 1/2a, 1/2b, 1/2c, 3a, 3b, 3c, 4a, 4ab, 4b, 4b(x), 4c, 4d, 4e, 7 þ

L.ivanovii 5 þþ

L. innocua 4ab, 6a, 6b, un



L.welshimeri 6a, 6b 

L.seeligeri 1/2b, 4c, 4d, 6b, un

þ

Portion of colony is stabbed into the blood plate.

Positive reaction.

Undefined.

Negative reaction.

3584

LISTERIA

/Listeriosis

can be seen. L. seeligeri has a similar appearance to

L. monocytogenes, except that a weaker zone of

hemolysis is observed. A wider zone of hemolysis

has been noted with L. ivanovii. As all strains of

Listeria are motile, tumbling motility (hanging drop

preparations from primary cultures isolated) can be

used to distinguish them from Erysipelothrix and

Corynebacterium species. One must remember that

Listeria is motile at room temperature (25



C), and

much less so or not at all at 37



0013 It is difficult to diagnose listeriosis infections in the

absence of culture isolation. While there are many

monoclonal antibodies available for the genus Listeria,

clinical use of these has been hampered owing to their

cross-reactivity with other bacteria. Serological studies

have shown that cross-reactivity to staphylococci, enter-

ococci, and corynebacteria can occur. Newer antibodies,

targeting the virulence factors, for example, may be

more useful in the clinical setting. Stool sample carriage

rates can range from 1 to 5%. As such, isolation of

L. monocytogenes from the stool may be helpful in

identifying Listeria gastroenteritis.

0014 Culture of L. monocytogenes from blood or CSF

does not require selective media, thus explaining why

blood agar plates are the medium of choice. However,

the isolation of specimens from food or environmen-

tal sources, stools, and vaginal secretions requires

selective media (as described in Figure 1). (See Micro-

biology: Detection of Foodborne Pathogens and their

Toxins.)

Antimicrobial Chemotherapy

0015 Because Listeria infections are often associated with

high mortality rates, it is imperative that effective

antibiotics be used for treatment. The current treat-

ment for listeriosis involves a combination of

ampicillin and gentamicin. Therapy for 2–3 weeks

appears to be sufficient to prevent relapses. Most b-

lactam antibiotics may be used. However, cephalos-

porins are not effective against L. monocytogenes and

should not be used to treat serious infections such as

neonatal meningitis. Other chemotherapeutic agents,

considered secondary treatments, include erythro-

mycin, fluoroquinolones, and vancomycin.

0016There have been reports of plasmid-encoded

resistance to antibiotics such as chloramphenicol,

erythromycin, streptomycin, and tetracycline. Tetra-

cycline resistance has been reported in 2–5% of

strains of L. monocytogenes. These resistant strains

have been shown to contain the tetM chromosomal

determinant (within a transposon). The tetM gene has

also been reported in L. innocua. Plasmid-mediated

resistance to tetracycline is due to a tetL (minocycline

sensitive) or tetS (minocycline resistant) gene. Inter-

estingly, the tetS gene, while first noted in the

genus Listeria, has been detected in Enterobacter

faecalis.

Prevention from Infection

0017There have been many outbreaks of listeriosis involv-

ing a wide variety of foods. Coleslaw, cold-smoked

salmon, delicatessen meats, hot dogs, pa

s, soft

cheese, and even pasteurized milk have been im-

plicated in major outbreaks. In addition, because

L. monocytogenes is ubiquitous in nature, it may

not be possible to eliminate it completely from the

food chain.

0018Many initiatives have been introduced by govern-

ment agencies in an attempt to ensure that foods are

safe. Newer technologies are also currently being

investigated as means of preventing the growth

of L. monocytogenes in foods. Irradiation is one

tbl0004 Table 4 Alternative methods for the identification and/or detection of Listeria monocytogenes

Name Type or format (target) Company/Supplier

Accuprobe L. monocytogenes DNA based (probe) GenProbe Inc.

BAX system DNA based (PCR) Qualicon

GENE-Trak DNA based (probe) Gene-Trak Systems

PROBELIA DNA based (PCR) Sanofi Diagnostics Pasteur

VIDAS Immunoassay based (enzyme linked fluorescent assay) bioMerieux Vitek

Listeria VIA Immunoassay based (ELISA) Tecra Diagnostics

Reveal (Listeria) Immunoassay based (immunochromatography) Neogen

ClearView Immunoassay based (immunochromatography) Oxoid

Assurance EIA (Listeria) Immunoassay based (ELISA) BioControl

EIAFOSS Listeria Immunoassay based (ELISA) Foss Electric

API Biochemical bioMerieux

Microbact Biochemical Microgen

Malthus Biochemical (conductance) Malthus

Microlog Biochemical (carbon oxidation) Biolog

MIS Biochemical (fatty acid) Microbial-ID

This is a partial list only and not meant as an endorsement by the authors.

LISTERIA

/Listeriosis 3585

example that has been approved for certain foods,

including meats, fruits, vegetables, and spices. (See

Irradiation of Foods: Basic Principles; Applications.)

0019 Numerous recommendations have been put forth

by many scientists and government agencies re-

garding ways to reduce the exposure to L. monocyto-

genes and the risk of foodborne listeriosis. These are

summarized in Table 5. The incidence of L. mono-

cytogenes in ready-to-eat foods ranges from 1 to

10%. It is certain, therefore, that most healthy people

around the world consume foods containing low

levels of this organism, without getting sick. Al-

though the minimum infectious dose (MID) for

L. monocytogenes is still unknown, if it were low,

one would expect many more cases of listeriosis to

be reported than are currently observed. Most coun-

tries do not have active human listeriosis surveillance

programs in place. It appears that the incidence of

human listeriosis is similar in countries with and

without a ‘‘zero tolerance’’ policy in place.

Mechanisms of Pathogenesis

0020 It is presumed that most infections of L. monocyto-

genes occur in the gastrointestinal (GI) tract, where

invasion is thought to occur. While it is believed to be

a resident of the GI tract for a short period of time,

there have been reports describing patients with a

long incubation time (up to 90 days) after eating

contaminated food. In this instance, the ability to

remain associated with the GI tract for extended

periods is still not clear or defined and is currently

an area of active research.

0021 There is much speculation on why most clinical

isolates belong to serovars 1/2a, 1/2b, and 4b; how-

ever, factual data in the form of animal studies or cell-

culture experiments are lacking. In 1979, Seeliger and

Hohne described a serotyping scheme for the genus

Listeria. According to this designation, the letters a,

b, c, etc. refer to the flagellar antigens. The numerical

aspect (i.e., 1/2, 3, 4, etc.) describes the somatic anti-

gens, being mostly techoic acid-associated (Table 3).

While much work has been done in the area of patho-

genesis, it is important to remember that these studies

have utilized the serotype 1/2a (e.g., strains 10403S,

EGD, NCTC7973, and Mack) or those belonging to

serotype 1/2c (LO28). Since serotype 4b is responsible

for a large number of reported outbreaks, it is quite

probable that significant differences exist when com-

pared to those serotypes currently being studied. For

example, several multilocus gel electrophoresis-based

studies have classified L. monocytogenes into two

genetic groups: one that includes ‘a’ and ‘c’ serotypes

(1/2a, 1/2c, 3a, and 3c) and another including the ‘b’

serotypes (1/2b, 3b, and 4b). Thus, while currently

known virulence factors seem to be a common denom-

inator in the pathogenesis of L. monocytogenes, cer-

tain class-specific host–pathogen interactions may

explain the tropisms observed related to serotype.

0022L. monocytogenes has proved to be an extremely

useful tool for examining protective immunity and

immune responses during systemic infections. Upon

ingestion of food contaminated with L. monocyto-

genes, the organism is believed to invade the intestinal

epithelium and/or Peyer’s patches. From here, the

bacteria enter the draining lymph node and dissemin-

ate via the bloodstream to the liver and spleen. In

most cases, infections of L. moncytogenes are limited,

with clinical symptoms appearing in the immuno-

compromised, pregnant women, and neonates. How-

ever, it is equally important to note that listeriosis has

one of the highest case fatality rates of all foodborne

bacterial infections.

0023Upon injection of the organism into the blood-

stream of mice, L. monocytogenes is usually cleared.

Studies have shown that over 60% of organisms are

taken up by the liver within 10 min of intravenus

inoculation, with hepatocytes being the major site of

replication in the liver. Hepatocytes contain over

90% of the organism after 6 h of infection.

tbl0005 Table 5 How to lower the risk of acquiring foodborne listeriosis

Group of interest Food item Recommendations

‘Normal’ individuals Meat, fish, poultry Cook all food of animal origin thoroughly

All foods Separate uncooked from cooked

Milk and milk products Avoid unpasteurized milk

Nonfood items Properly wash hands, knives, and kitchen utensils

Fruits and vegetables Wash all fruits and raw vegetables prior to consumption

High-risk

(elderly, pregnant,

or immunocompromised)

individuals

Dairy products Do not consume soft cheeses such as Brie, Camembert or feta

(hard cheese, cottage, processed and yogurt are OK)

Leftovers Heat thoroughly to 70



C for a minimum of 2 minutes

Hot dogs/wieners Heat to 70



C for a minimum of 2 minutes

Deli meats Avoid unless thoroughly heated

Should be avoided

3586

LISTERIA

/Listeriosis

0024 The innate component of the immune system is

responsible for controlling the replication of the or-

ganism during the first 3 days of infection, based on

studies performed in mice. This response will either

eliminate the organism or prevent sepsis. The T-cells,

part of the cell-mediated immune system, mediate a

protective primary as well as a memory response to

L. monocytogenes. Within the liver, macrophages

known as Kupffer cells are believed to trap the major-

ity of Listeria that enter. However, it has been shown

that over 90% of liver bacteria are associated with

hepatocytes, and not Kupffer cells. Currently, it is

believed that there is a physical interaction between

the Kupffer cells and neutrophils that is mediated via

intercellular adhesion molecule-1, thereby promoting

resistance against L. monocytogenes. Chemokines

and other adhesion molecules cause the efflux of

neutrophils and monocytes from the bone marrow

to the peripheral blood, probably via interleukin-6

and macrophage colony-stimulating factor stimula-

tion, respectively.

0025 L. monocytogenes is considered an intracellular

pathogen because it is able to enter a host cell, move

across the cell cytoplasm, and enter neighboring cells

without ever becoming extracellular (Figure 2). The

infection process begins with the internalization of

the organism into cells that may or may not be phago-

cytic. In the case of phagocytes such as macrophages,

the phagocytosis process itself causes the organism to

be taken within. For nonphagocytic cells, induced

phagocytosis (known as invasion) occurs. The plasma

membrane envelops the bacteria upon contact. The

bacteria reside within membrane-bound vacuoles

prior to lysing of the vacuolar membrane. Once free

within the cell cytoplasm, Listeria are able to repli-

cate and become covered with host actin filaments.

The host actin filaments are rearranged to a polar tail,

consisting of short actin filaments and other host

proteins. The formation of the actin ‘tail’ at one end

of the organism ‘propels’ it to move through the

cytoplasm. As the organism nears the cell membrane,

it protrudes and neighboring cells internalize them

upon contact. In this manner, L. monocytogenes is

able to move from one cell into another without

being exposed to the ‘outside’ environment. Once in

a neighboring cell, the bacterium is contained in a

double plasma membrane, one from the previous

cell (while protruding outward from the membrane)

and one from the new cell (as it takes in the organism

via phagocytosis).

0026The bacterium is able to internalize itself through

the action of at least two proteins, internalin A (InlA)

and internalin B (InlB). Currently, two pathways have

been proposed for entry into mammalian cells. The

first is the internalin-E-cadherin pathway, in which

the invasin from L. monocytogenes interacts with

the b-1-integrin adhesion molecule thought to be

connected to the cytoskeleton. The second pathway

is InlB-dependent, sharing similarities with the

growth-factor-mediated signaling pathways. InlB

has recently been shown to bind the extracellular

domain of MET (also known as the hepatocyte

growth factor (HGF)), a receptor tyrosine kinase.

Upon binding to MET, InlB is proposed to cause a

‘scattering’ of epithelial cells. The protein p60, en-

coded by the gene iap, has been shown in experiments

to be essential in the invasion process. Deletion of the

iap gene is lethal. Believed to be a mureine hydrolase,

its role is still unclear. What is known, however, is

that cells producing reduced levels of p60 show a

‘rough’ morphology and exhibit reduced adherence,

invasiveness, and virulence.

0027The bacterium is able to escape the vacuolar

membrane through the action of listeriolysin O, a

pore-forming toxin encoded by the gene hylA. Phos-

phatidylinositol-phospholipase C, a member of the

pore-forming family of thiol-activated cytolysins,

also contributes to the organism’s ability to escape

the vacuole. ActA is a surface protein with a mem-

brane anchor at its carboxyl-terminal end. Its amino-

terminal has been shown to be essential for actin

Escape from double

vacuolar membrane

(plcB/hylA/mpl )

Escape from vacuole

(hlyA, plcA)

Phagocytosis of L. monocytogenes

(inlA/inlB/iap)

Travel within

cytoplasm (act A)

Protrusion into

neighboring cell

(act A)

Repeat cycle

fig0002 Figure 2 Proposed mechanism of entry into mammalian cells

by L. monocytogenes. The genes implicated are listed.

LISTERIA

/Listeriosis 3587

assembly. ActA is responsible for the intracellular

actin-based motility. It is believed that ActA is able

to recruit the host actin filaments and make them

assemble at one pole of the bacterium. This actin

tail formation would then be the driving force in

the intracellular movement observed using micro-

scopy technology. The lecithinase PlcB acts on the

double-membrane vacuole that the bacteria faces

when it reaches its neighboring cell. PlcB is synthe-

sized as a precursor and is cleaved by a zinc metallo-

protease, shown to be encoded by the mpl gene.

Listeriolysin is also implicated in escape from the

second vacuole.

0028 Regulation of the virulence genes that allow for

intracellular movement, and thus escape from the

immune surveillance system, all fall under the pleio-

tropic activator, PrfA (Figure 3). Encoded by the gene

prfA, PrfA is able to regulate the expression of many

of the virulence genes described, including plcA,

hlyA, mpl, actA, and inlAB. A 27-kDa protein,

PrfA, has been shown to activate the transcription

of these genes and has been shown to be a DNA-

binding protein (Figure 3).

0029 The regulation of prfA itself is complex. It has been

shown that at temperatures below 30



C, PrfA-

dependent genes are not transcribed, since there is a

lack of prfA transcription. Shifting the temperature to



C causes expression (transcription, translation) of

the prfA gene, which in turn activates the virulence

gene cluster. Addition of activated charcoal to a cul-

ture medium also has the same effect. Presumably, the

charcoal somehow sequesters a signal molecule,

which permits the transcription of prfA and, thus,

the virulence genes. Increasing glucose concentrations

in the medium turn off virulence gene expression, by

directly influencing the expression of prfA. While the

prfA gene product appears to auoregulate its own

expression and synthesis, there is certainly more to

the complexity of regulation of virulence genes and

their prime activator, PrfA. A member of the cyclic

AMP (cAMP) receptor protein (CRP)/FNR (regulator

of fumarate and nitrate reduction) family of bacterial

regulators, it is currently believed that PrfA is a

regulatory protein that binds its symmetric target

sequence and enhances (or, alternatively, inhibits)

the binding of RNA polymerase, thereby influencing

transcription. The Crp (or catabolite activator pro-

tein) is a regulatory protein that modulates the ex-

pression of genes involved with catabolite repession,

whereas the Fnr family has been shown to regulate

the cellular response to anaerobic growth.

See also: Irradiation of Foods: Basic Principles;

Applications; Microbiology: Detection of Foodborne

Pathogens and their Toxins

Further Reading

Charpentier E and Courvalin P (1999) Antibiotic resistance

in Listeria spp. Antimicrobial Agents and Chemotherapy

43: 2103–2108.

Cousens LP and Wing EJ (2000) Innate defenses in the liver

during Listeria infection. Immunological Reviews 174:

150–159.

Farber JM and Peterkin PI (1991) Listeria monocytogenes,

a food-borne pathogen. Microbiological Reviews 55:

476–511.

Goebel W and Kuhn M (2000) Bacterial replication in the

host cell cytosol. Current Opinion in Microbiology 3:

49–53.

Janda JM and Abbot SL (1999) Unusual food-borne patho-

gens: Listeria monocytogenes, Aeromonas, Plesiomo-

nas, and Edwardsiella species. Clinics in Laboratory

Medicine 19: 553–582.

Tage AJ (1999) Listeriosis: recognizing it, treating it, pre-

venting it. Cleveland Clinic Journal of Medicine 55:

375–380.

Temple ME and Hahata MC (2000) Treatment of listeri-

osis. The Annals of Pharmacotherapy 34: 656–661.

prf A

inl A inl B iap

plc A mplhly A act A plc A

1 kb

Prf A

fig0003 Figure 3 PrfA, the master regulator of most virulence genes

found on the chromosome of L. monocytogenes.

3588

LISTERIA

/Listeriosis

LITHIUM

M Anke, U Scha

fer and W Arnhold, Friedrich-

Schiller-Universitat, Jena, Germany

History, Nature, and Function

0001 Lithium (Li) is the lightest alkali metal (atomic weight

6.94). It shows physicochemical anomalies which

result from the unexpectedly great difference between

the electronegativity of this element and that of

sodium, potassium, and rubidium. These differences

are seen in both the properties and the reactions of

this silvery white metal which was discovered by

Arfvedson (1818) in Berzelius’s laboratories. The

new alkali element was detected when a fossil

known as petalit was analyzed. It was called lithion

(stone) because it was first found in the mineral

kingdom.

0002 The Earth’s crust contains 50–65 mg lithium kg

1

The geological origin of the soil is reflected in its

lithium content. The plants of slate, keuper, and

gneiss weathering soils are richer in lithium than

those of diluvial and alluvial formations (Table 1).

Therapy and Toxicity

0003 In 1843, lithium carbonate was introduced into the

materia medica as a new solvent for stones in the

bladder by the surgeon Ure. In 1859, the internist

Garrod recommended a therapy with lithium salts

for a wide range of diseases and complaints,

especially gout, urinary calculi, rheumatism, mania,

depression, and headache. All of them were grouped

under the general heading of the uric acid diathesis

which became a major unifying medical principle for

almost a century. In 1941, however, this hypothesis

was declared to be ill-founded.

0004The fascinating discovery of the specific antimanic

effect of the lithium cation by the psychiatrist Cade in

1949 initiated the career of this chemically simple

drug as a very potent substance against symptoms of

manic-depressive illness. After numerous hindrances

due to the lack of knowledge of its biochemical and

pharmacokinetic properties had been overcome, lith-

ium developed into a safely used psychopharmaco-

logical agent. Improvements in its monitoring,

especially by the introduction of the lithium ion-

selective electrode, as well as in patient compliance

with medication, were also decisive. It was possible

to extend the classical antimanic, antidepressive and

recurrent-prophylactic action profile of lithium by an

antipsychotic, antiaggressive, antisuicidal, and anti-

neurotic component. Recently, topical lithium has

found employment in dermatological disorders, e.g.,

seborrheic dermatitis and herpesvirus infections. It is

promising that further applications of lithium as an

antiinflammatory, antiviral, antifungal, antitumor,

and immunomodulating agent, e.g., in the treatment

of acquired immune deficiency syndrome (AIDS) and

cancer, may become established in the future. The

characteristic pharmacologically rare properties of

the drug lithium are that it does not lose efficacy

and does not induce addiction and dependence.

Thus, a ‘mechanical switch-on and -off function’ in

its biochemical mechanism is discussed.

0005However, lithium therapy (lithium exposure) also

induces side-effects in the form of thyroid changes,

nephrogenic diabetes insipidus, cardiovascular dis-

turbance, epithelial damage, changes in carbohydrate

metabolism, and skeletal damage in the form of bone

mineralization. Patients treated with lithium usually

tend to gain weight. It must be emphasized that the

lithium dosage of 24–48 mmol or 167–333 mg day

1

(0.5–1.5 mg day

1

serum lithium) now used in humans

is relatively high compared with the effects registered

in animals. In rats, chickens, hens, pigs, and bulls,

50–100 mg lithium kg

1

ration dry matter reduced

the feed consumption significantly. All lithium-

exposed pigs took in considerably more water than

control animals. The same is apparently true for

humans treated with lithium, who meet these high

fluid requirements with high-caloric beverages and

thus consume more energy.

tbl0001 Table 1 The site-specific lithium content of indicator plants as a

percentage of the site richest in lithium

Site Relative number

Sandstone weathering soils of chalk formation 100

Slate 94

Keuper 94

Gneiss 92

Muschelkalk 83

New red sandstone (Bunte) 83

Lower strata of new red sandstone (Rot-bigende) 70

Diluvial sands 72

Granite 72

Loess 71

Syenite 68

Phyllite 65

Moor, peat 58

Boulder clay 54

Alluvial riverside soils 51

LITHIUM 3589

0006 All species with > 100 mg lithium kg

1

feed dry

matter reduced life weight gain and egg production.

Ruminants seem to be equally sensitive to lithium

exposure. Lithium applications from 10 mg kg

1

feed dry matter upwards led to a significantly higher

suet content.

0007 The lower sexual aggressiveness of bulls receiving

100 and 200 mg lithium kg

1

ration should also be

mentioned. Rats with lithium-rich ration gave birth

to lighter offspring which developed more slowly.

0008 All pigs receiving 1000 mg lithium kg

1

feed dry

matter died within 92 days. Cases of death also

occurred in animals on 500 mg lithium kg

1

feed

dry matter.

Essentiality

0009 Plants There are considerable differences in the tol-

erance of various plant species to lithium and in their

ability to take up this element. Solanaceae are known

to have the highest tolerance to lithium. Some

members of this family accumulate more than 1000

p.p.m. lithium. On the other hand, citrus trees are the

most susceptible to injury by an excess of lithium,

which is reported to be toxic at a concentration of

140–220 p.p.m. in the leaves. In Russia, the beneficial

effects of lithium are still used in agriculture. Lithium-

containing fertilizers lead to increased starch levels

and biomass in potatoes. The observed lithium-

induced growth stimulation seems to allow the evalu-

ation of lithium as an agrochemical. However, it is

still not proven that lithium is an essential nutrient or

an active substance for plants because they can com-

plete their life cycle without this element. Lithium

must rather be considered a toxic substance, with

marked species-dependent differences in sensitivity.

There is no proof yet that lithium is essential for

plants. Lithium must rather be regarded as potentially

phytotoxic.

Animals

0010 Whether lithium is essential for fauna has been inves-

tigated systematically since 1976 in goats, sheeps, and

rats in Germany, in Hungary, in the USA, and in

Japan. The influence of a lithium-poor ration on the

pre- and postnatal growth of goats was tested in 13

experiments over 13 years. It was shown that the

kids of lithium-deficient goats had a 9% lower

birth weight than those of control goats. In lithium-

deficient rats the litter was 20–30% smaller in

comparison to control animals. Moreover, the lith-

ium-poor nutrition caused reproductive disorders in

goats and rats. Lithium-poor rations of female goats

did not have an effect on the intensity of estrus behav-

ior. The first mating, however, produced a significantly

worse rate of conception in these animals. Repeated

services at the following ovulations improved the

conception rate of lithium-deficient goats. The differ-

ence between the groups remained significant.

0011The increased abortion rate of lithium-deficient

goats is also important. Miscarriages occurred at a

rate of 14% between the third and fifth month of

gravidity. The effect of lithium deficiency on sex

ratio was most surprising. As a rule, hornless goats

give birth to more male than female kids. Lithium-

deficient goats, however, gave birth to significantly

more female kids. The 5-year average showed that

lithium-deficient goats produced 20% less milk than

control animals.

0012Long-term lithium deficiency experiments with

female goats allowed the analysis of the influence of

the lithium-poor nutrition on the life expectancy of

the animals. The investigations showed that 41% of

lithium-deficient goats and 7% of control animals

died during the first year of the experiments. Skin

lesions occurred in individual animals with lithium-

poor rations. In the meantime, it was shown, that

lithium was also effective in the treatment of herpes-

virus infections and of seborrheic dermatitis in

humans.

0013Lithium deficiency did not affect the biochemical

blood profile, but it changed the activity of several

serum enzymes. As a rule, lithium deficiency reduced

the serum enzyme activity, mainly the enzymes of

the citrate cycle (ICDH, isocitric acid dehydrogenase;

MDH, malate dehydrogenase), of glycolysis (ALD),

and of nitrogen metabolism (GLDH, glutamine

dehydrogenase), for which significant differences

between control and lithium-deficient goats occurred.

Only creatine kinase, a stress indicator enzyme, was

significantly increased in lithium-deficient goats.

0014Owing to the particular role of monoamine oxidase

(MAO) in manic-depressive diseases, chronic schizo-

phrenia, and unipolar depression, this enzyme was

also investigated in the liver of control and lithium-

deficient goats. MAO activity in the hepatic tissue of

the latter group was reduced by 28%.

0015Abnormal behavior was observed in lithium-

deficient rats, and this disappeared after lithium sup-

plementation. This assessment is interesting in so far

as the MAO hypothesis is discussed as a biochemical

mechanism of lithium effect in humans. In brief, the

results of a lifelong lithium-poor nutrition over > 10

generations of goats show that lithium may be essen-

tial to fauna, and thus, to humans as well.

Lithium in the Diet

0016The lithium intake of adult humans with mixed diets

was systematically investigated in 10 test populations

3590 LITHIUM

of 7 women and 7 men, each from different regions

of Germany and aged between 20 and 69 years

(Table 2).

0017 Men and women consumed the same amount of

lithium-rich and lithium-poor foods and beverages.

The lithium intake of both sexes doubled after the

reunification of Germany and worldwide trade. Since

men consume 24% more dry matter than women,

they take in more lithium than women. The distri-

bution of the individual lithium intake does not

follow the Gaussian curve but it is shifted to the left

(Figure 1). The lithium consumption was character-

ized by an extreme variation range, which may be

caused by water and beverages.

0018 Adults of both sexes with mixed diets consumed

significantly more lithium with increasing age. On

average, elderly test persons consumed 30–46%

more lithium. They clearly preferred lithium-rich

foodstuffs. The lithium intake per day on individual

sites varies between 200 and 2400 mg day

1

on aver-

age. The postulated potential lithium requirement of

100 mgday

1

is met on the average of the population.

Ten percent of the men tested consumed < 100 mg

lithium day

1

as a weekly average. Worldwide, a lith-

ium intake for adults between 660 and 3420 mg day

1

is calculated.

The Lithium Content of Foodstuffs and

Beverages

0019The lithium content of water seems most likely as an

explanation for the different lithium intake. Water

from swamp and peat sites contained eight times

more lithium than that from diluvial sands (Table 3).

In addition, a relationship between high lithium con-

tents in drinking water on the one hand and low rates

of crimes, suicides, and arrests on the other was

controversially discussed.

0020In line with the low lithium content of cereals, flour

and other cereal products contained little lithium.

Honey and sugar are also extremely poor in lithium.

Ready-to-serve soups with meat and eggs were richer

in lithium, whereas various puddings, macaroni, and

vermicelli usually contained < 1 mg lithium kg

1

dry

matter (Table 4).

0021Bread, cake, and pastries are usually poor sources

of lithium. On average, they contained less lithium

than wheat flour. The addition of sugar apparently

leads to a further reduction of the lithium content in

bread, cake, and pastries.

0022All vegetables and potatoes contain > 1.0 mg lith-

ium kg

1

dry matter. Peeling potatoes decreases their

lithium content, as potato peel stores more lithium

tbl0002 Table 2 Lithium intake of German adults with mixed diets

depending on time (mg day

1

)

Year (n;n) Women Men Fp %

SD xxSD

1988 (196; 196) 444 374 419 432 < 0.01 112

1992 (294; 294) 724 713 990 1069 139

Fp < 0.001 

191 236

Women ¼ 100%, men ¼ x%;

1988 ¼ 100%, 1992 ¼ x%.

x, arithmetical mean;

SD, standard deviation; n, number; Fp, significance

level in one or multiple factorial variance analysis.

125

375 625 875 1125 1375 1625 1875 2125 2375 2625 2875 3125 3375

12201575211321001

fig0001 Figure 1 The mean weekly lithium intake of men in mg day

1

tbl0003Table 3 The lithium concentration (mgl

1

) of drinking water

from different geological sources

Source of water Mean

New red sandstone (Bunte) 4.2 3.4

Gneiss 4.3 4.8

Phyllite 6.9 3.4

Diluvial sands 7.7 5.8

Slate 11 10

Boulder clay 19 22

Syenite 22 18

Ioess 27 23

Muschelkalk, keuper 34 26

Lowland swamps 60 20

LITHIUM 3591

than the inner part of the potato that is commonly

eaten.

0023 As a rule, fruits contain less lithium than vegetative

parts of plants (vegetables). Lemons and apples

contained significantly more lithium, with about

1.4 mg kg

1

dry matter, than peas and beans, which,

like the different kinds of cereals grains, are extremely

lithium-poor as seeds.

0024 Owing to the small amounts used in their applica-

tion, spices do not contribute much lithium to the

diet. It is surprising that mustard is relatively

lithium-rich, with 3.4 mg kg

1

dry matter, whereas

mustard seed contains extremely little lithium.

0025 Various semiluxury foods usually provide only

modest amounts of lithium. The total amount in tea

and coffee, not their water-soluble fraction in the

beverage, was registered. Their low lithium content

indicates that insignificant amounts of lithium enter

the diet via these beverages. The lithium content of

chocolates, chocolate candies, and sweets amounted

to about 0.5 mg kg

1

dry matter. Cocoa is somewhat

richer in lithium. The addition of sugar in chocolates

reduces their lithium content.

0026 On average, eggs, meat, sausage, and fish deliver

significantly more lithium per kg of dry matter than

most cereal foodstuffs. Eggs, liver, and kidneys of

cattle had a mean lithium content of 5 mg kg

1

. Beef

and mutton contain more lithium than poultry meat.

Green fodder and silage consumed by cattle and sheep

are much richer in lithium than the cereals largely fed

to poultry. Sausage and fish contain similar amounts

of lithium to meat. There were significant differences

between the lithium content of milk: milk contains a

high lithium concentration of 10 mg kg

1

dry matter.

0027 In contrast to milk, curd cheese and other cheeses

only retain 20–55% of lithium in the original material

available for human nutrition. The main fraction of

lithium certainly leaves cheese and curd cheese via the

whey. Like margarine made of plant fat, butter is also

lithium-poor, with 1.2 mg kg

1

dry matter.

0028 The fact that lithium is easily soluble may also be

the reason for the high lithium content of beverages.

Cola and beer deliver considerable amounts of lith-

ium for humans, and this must be taken into consider-

ation when calculating the lithium balance of humans.

Identification of Lithium Status

0029As already demonstrated in the literature, blood

serum best reflected lithium status, followed by hair.

Milk reflects the lithium status well. Lungs, spleen,

and carpal bones also reflected the different lithium

supply. Other parts of the body indicated the lithium

status only insignificantly and the cardiac muscle not

at all.

Determination of Lithium

0030Lithium may be determined in foods and biological

samples with the same techniques employed for

sodium and potassium. However, the much lower

levels of lithium compared with these other alkali

metals, mean that techniques such as flame photom-

etry often do not show adequate sensitivity. Flame

(standard addition procedure) or electrothermal

atomic absorption spectrophotometry are the most

widely used techniques after wet or dry ashing of

the sample. Corrections may have to be made for

background/matrix interferences. Inductively coupled

plasma atomic emission spectrometry is not very

sensitive for this very low-atomic-weight element.

See also: Sodium: Properties and Determination