Opinion
Vitamin C Deficiency and Scurvy Are Not Only a Dietary Problem
but Are Codetermined by the Haptoglobin Polymorphism
Ascorbic acid (vitamin C) is prone to oxidation in vivo.
The human plasma protein haptoglobin (Hp) shows a
genetic polymorphism with 3 major phenotypes (Hp 1-1,
Hp 2-1, and Hp 2-2) that show important functional
differences. Despite an adequate nutritional supply, in
Hp 2-2 individuals (most common among Asian populations) vitamin C is markedly lower in concentration
and particularly prone to oxidation in vivo. Therefore,
susceptibility to subclinical and clinical vitamin C deficiency (scurvy) is partly genetically determined. The
genetic advantage of the Hp1 allele as a vitamin C
stabilizing factor helps to elucidate the direction and
successes of long-distance sea crossing human migrations in history. Clinical trials demonstrated Hp phenotype–related effects of antioxidant treatment. Because
vitamin C is a first line antioxidant, Hp polymorphism
and its effects on vitamin C have major clinical consequences; a marked difference in genetic susceptibility
toward atherosclerosis between Hp phenotypes is attributable to variation in LDL oxidation. The classical
view of vitamin C and scurvy being a pure nutritional
condition needs to be updated. These findings should
foster research investigating the role of Hp polymorphism in human disease, and in vitamin C deficiency
and atherosclerosis in particular.
© 2007 American Association for Clinical Chemistry
Humans cannot synthesize the chemically unstable ascorbic acid (vitamin C). On average, the human body loses
⬃3% of its vitamin C content per day, which shortens the
disease-free and survival time in individuals on a diet low
in vitamin C. Vitamin C deficiency and scurvy have been
major health problems throughout human history, and for
ages human migration and seagoing voyages have been
plagued with scurvy (1 ). The in vivo instability of vitamin
C is due to its proneness to oxidation, particularly in the
presence of transition metal ions such as iron and copper.
Vitamin C is a 1st-line antioxidant acting as a free radical
scavenger. Although scurvy is generally regarded as a
nutritional problem, correlation between vitamin C intake
and vitamin C concentration is rather weak (r ⫽ 0.42);
only ⬃17% of the variance of the serum vitamin C
concentration can be explained by vitamin C intake (2 ).
Vitamin C status is determined not only by the dietary
vitamin C content, but also by environmental and lifestyle
factors (e.g., smoking), biological factors (e.g., inflammation, iron excess), and pathological conditions (e.g., malabsorption, hemolysis). Clinical and in vitro studies have
demonstrated that the genetic polymorphism of the abundant plasma protein haptoglobin (Hp) may play a role.
Because of the presence of 2 codominant alleles (Hp1 and
Hp2), 3 major haptoglobin phenotypes are known in man:
Hp 1-1, Hp 2-1, and Hp 2-2 (3 ). The stability of vitamin C
in serum is lowest in Hp 2-2 individuals (4 ). This finding
has major consequences in several medical problems and
may offer explanations to intriguing historical questions.
This report summarizes the evidence for the thesis that
the Hp polymorphism is an important nonnutritional
modifying factor in the pathogenesis of vitamin C deficiency and scurvy.
vitamin c metabolism and hp polymorphism
The major biological function of Hp is binding and
recycling of free hemoglobin (Hb) in plasma to prevent
oxidative damage induced by heme iron after hemolysis
(3 ). Hp phenotypes show important structural and functional differences. Hp 1-1 is an 86-kDa dimeric molecule,
whereas Hp 2-1 and Hp 2-2 show polymeric forms (up to
900 kDa). The capacity of Hp 2-2 to inhibit Hb-driven
lipid oxidation and vitamin C depletion is inferior to that
of Hp 1-1 (4 ). In vivo, the antioxidative capacity (ascorbic
acid stability) is low in Hp 2-2 individuals because the
ability of Hp 2-2 polymers to sieve into the extravascular
compartment is restricted by their high molecular mass.
Complexes of Hb and multimeric Hp 2-2 are endocytosed
by the CD163 receptor on monocyte-macrophages (5 ).
Parts of Hb-derived iron are delocalized and accumulate
in inert, poorly accessible iron storage compartments
(5, 6 ). Cytosolic ferritin content is twice as high in monocyte-macrophages from Hp 2-2 individuals compared
with Hp 1-1 and 2-1 individuals (6 ). Vitamin C reduces
Fe3⫹ to Fe2⫹ in the ferritin crystal core, a reaction in which
ascorbic acid is oxidized. The released Fe2⫹ promotes the
production of highly reactive hydroxyl radicals (Fenton
chemistry), which deplete vitamin C stores in Hp 2-2
individuals (4 ). Lower serum ascorbic acid concentrations have been observed in European and Chinese individuals with the Hp 2-2 phenotype (4, 7 ). The effect of
Hp polymorphism on vitamin C concentration is of the
same magnitude as the effect of nutritional intake (4 ).
Fig. 1 summarizes the Hp-related effects on vitamin C
metabolism.
geographical distribution of hp phenotypes
The human Hp2 allele originated in South Asia as a result
of partial duplication by unequal crossing-over between
Hp1 alleles (3 ). South-East Asian populations show the
highest frequencies of the Hp2 allele and the lowest of the
wild-type Hp1 allele (⬃0.25). Humans are currently in a
state of transient gene equilibrium, in which the Hp2
allele has been generally favored during evolution.
Among Western European populations, Hp1 and Hp2
allele frequencies are ⬃0.40 and 0.60, respectively. Indigenous Latin American populations are characterized by
Clinical Chemistry 53, No. 8, 2007
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Delanghe et al.: Hp Polymorphism, Vitamin C Deficiency, and Scurvy
very high (0.58 – 0.78) Hp1 allele frequencies (3 ). Amerind
populations showing very high Hp1 allele frequencies
amazingly proved their ability to cross the ocean on
simple rafts without any advanced shipbuilding knowledge or technology (8 ). The advantage of Hp1-1 as a
genetic factor favoring survival in long-distance sea voyages is illustrated by the Hp phenotype distribution
among the indigenous populations of remote islands.
Easter Island is one of the remotest places on earth. Its
indigenous Rapa Nui population is characterized by the
highest Hp1 allele frequency (0.86) known (2 ). Undoubtedly, early immigrants of Easter Island were subjected to
challenging vitamin C depletion (scurvy) during the long
Fig. 1. The effects of haptoglobin polymorphism on vitamin C
metabolism.
In individuals carrying the Hp 2-2 type, ascorbic acid is more prone to oxidation
at different levels. (a) Free Hb, continuously released from erythrocytes, is
recycled by the formation of Hb-Hp complexes, which are transported to the liver,
a pathway contributing to normal iron turnover. Hp 2-2 polymers are less efficient
inhibitors of Hb-driven oxidative stress, leading to ascorbic acid depletion. (b),
complexes of Hb and multimeric Hp 2-2 are selectively taken up by the CD163
receptor on monocyte-macrophages, leading to accumulation of heme-derived
iron as intracellular ferritin. Vitamin C reduces Fe3⫹ to Fe2⫹ in the ferritin crystal
core, a reaction in which ascorbic acid is oxidized, and the released Fe2⫹
promotes the production of reactive hydroxyl radicals (Fenton reaction), which
can further deplete vitamin C in Hp 2-2 individuals. AA, Ascorbic acid; AA•,
ascorbate radical; Hb, hemoglobin; Hp, haptoglobin; RBC, erythrocytes.
voyage on the Pacific Ocean. Similarly, Madagascar has a
mixed population of African and proto-Indonesian origin.
The Hp1 allele frequency of the island’s population is
remarkably higher than those of the constituting founding
populations (9 ), a finding that pleads the case for genetic
selection based on Hp phenotype during the migration.
historical findings
Early literature on scurvy relied mainly on Western
sources, and thus the traditional view of scurvy was
narrowed to a health problem of European seagoing
nations. However, a detailed review of non-Western historical sources revealed that scurvy was a major health
issue in East and South-East Asians as well (10 ), a finding
that can be reconciled with the fact that South-East Asian
populations show very high Hp 2 allele frequencies (e.g.,
Chinese and Japanese: ⬃0.75) and that the Hp 2 allele is
associated with a higher in vivo vitamin C instability.
Despite the advanced development and technology in
navigation, shipbuilding, cartography, and even the use
of empirical antiscorbutic preventive dietary measures in
China during the Ming era (1368 –1644) (10 ), the Chinese
seagoing expeditions led by Admiral Zheng He (1371–
1433) suffered from extremely heavy casualties and were
finally discontinued (10 ). Clinical cases of scurvy occurred frequently among the Chinese garrisons operating
beyond the Great Wall (10 ). Fig. 2 shows an 18th century
Chinese description of scurvy (11 ).
In the mid-19th century, scurvy was extremely common among Chinese migrant workers crossing the Pacific
to California (10 ). In addition, Japanese sailors were
particularly susceptible to scurvy during drifting accidents in the Pacific. In early modern Japan (19th century),
there is a description of the Tsugaru soldiers with up to
72% mortality from scurvy (12 ). Among castaways, mortality rates as high as 50% and 78% have been reported in
19th century records (13 ).
For Europeans, relative losses by scurvy were lower
than for Asians. The French expedition of Cartier in 1536
counted 25 victims (a rate of ⬃30%) (1 ). For the Dutch
East Indies Company, typical crew losses for a 1-way trip
between Europe and the Indonesian archipelago in the
17th century were ⬃20%. The Dutch expedition to
Novaya Zemlya in 1596 counted only 2 scurvy victims
among 17 crew members. In the Crimean War (1854 –
1856), the French Navy counted ⬃30% of scurvy cases (1 ).
In Perth general prison in Scotland, during 1845–1846
scurvy occurred at a rate of 50 of 330 inmates. In 1819, 160
scurvy victims were counted of 800 soldiers in the US
Army outpost at Fort Atkinson (Nebraska) (1 ). In 1864,
during the US Civil War, Andersonville prison counted
3000 scurvy deaths among 30 000 prisoners (1 ). Despite
the fact that conditions are not completely comparable,
these data are striking because they were recorded in
relative homogeneous populations sharing a uniform
diet. The relative number of victims roughly corresponds
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Clinical Chemistry 53, No. 8, 2007
with the relative frequency of the Hp 2-2 phenotype
among populations of European ancestry (3 ).
The effect of the Hp polymorphism on vitamin C
metabolism offers a plausible explanation as to how,
during the course of human history, some populations
characterized by a high Hp1 allele frequency have been
able to migrate successfully over long distances and some
genetically privileged nations (in terms of vitamin C
stability) could advance to colonizing empires with a
global presence. Apart from cultural, technological, and
political variables, genetic and biochemical influences
such as Hp polymorphism may have played a major role
in human mass migration, in which some populations
may have been more favored than others.
clinical findings
The effect of Hp phenotypes on in vivo vitamin C stability
may have important consequences in a variety of clinical
conditions related to oxidative stress, particularly atherosclerosis. Circulating concentrations of oxidized LDL,
which play a key role in atherogenesis, are higher in male
Hp 2-2 individuals (14 ). The beneficial effect of oral
antioxidant supplementation (containing supraphysiological doses of ascorbic acid and other antioxidants) on
LDL oxidation was more pronounced among Hp 1-1
individuals (15 ). The differences in iron status and susceptibility to LDL oxidation among Hp 2-2 individuals
helps to explain why communities from the Indian subcontinent (with high Hp 2 allele frequency) develop more
atherosclerosis when exposed to a modern western lifestyle. The Hp 2-2 phenotype is overrepresented in whites
suffering from cardiovascular disease (3 ). Discrete biochemical signs of subclinical vitamin C deficiency have
been observed in peripheral arterial disease patients with
pronounced inflammation, despite a largely sufficient
nutritional supply of vitamin C (16 ). Clinicians should be
aware that patients presenting with an Hp 2-2 phenotype
(in whites typically ⬃35% of the population, in South- and
East-Asians, ⱖ50%) genetically are more prone to develop
subclinical scurvy in the case of inflammation-associated
oxidative stress conditions.
conclusions
The classical view of vitamin C deficiency and scurvy
being exclusively nutritional disorders (postulated by
Szent-Györgyi more than 70 years ago) needs to be
updated. Despite the promising predictions from in vitro
studies, overall results of clinical trials with supraphysiological supplements of vitamin C and other antioxidants
have not been very convincing (17 ), possibly because of
genetic variation within the investigated study populations. Stratifying patient outcome according to Hp phenotype in such studies could potentially give a more
differentiated picture. These approaches may result in
disease treatments better tailored to diseases in which the
redox state of the patient plays a role.
Grant/funding support: This work has been supported
by the own research fund (BOF) of Ghent University
(B/00145-BOF/2-4/BOF2002).
Financial disclosures: None declared.
Acknowledgments: We thank Prof. B. Dessein and Prof. A.
Heirman for their helpful discussions.
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Fig. 2. An 18th century drawing of a Qing soldier suffering from scurvy
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Joris R. Delanghe1*
Michel R. Langlois1
Marc L. De Buyzere2
Mathieu A. Torck3
1
Department of Clinical Chemistry
University Hospital Ghent
Ghent, Belgium
2
Department of Cardiology
University Hospital Ghent
Ghent, Belgium
3
Department Languages and Cultures
of South and East Asia
Ghent University
Ghent, Belgium
* Address correspondence to this author at: Department of
Clinical Chemistry, University Hospital Ghent, De Pintelaan 185
(2P8), B-9000 Ghent, Belgium. Fax 32-9-240-4985; e-mail joris.
[email protected].
DOI: 10.1373/clinchem.2007.088658