Hereditary haemochromatosis type 1 (HFE-related Hemochromatosis)
is a
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
characterized by excessive intestinal absorption of
dietary iron, resulting in a pathological increase in total body iron stores.
Human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s, like most
animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
s, have no means to excrete excess iron,
with the exception of
menstruation
Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of hor ...
which, for the average woman, results in a loss of 3.2 mg of iron.
Excess iron accumulates in tissues and organs, disrupting their normal function. The most susceptible organs include the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
,
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
,
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
,
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
,
joints
A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw- ...
,
gonads
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sperm ...
,
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
and
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
; patients can present with
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
,
polyarthropathy
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
,
hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
,
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, or
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
.
[https://www.cdc.gov/genomics/disease/hemochromatosis.htm. Centers for Disease Control and Prevention]
There are 5 types of hereditary hemochromatosis: type 1,
2 (2A, 2B),
3,
4[ and 5,] all caused by mutated genes. Hereditary hemochromatosis is the most frequent, and unique related to the HFE gene
Human homeostatic iron regulator protein, also known as the HFE protein (High FE2+), is a protein which in humans is encoded by the ''HFE'' gene. The ''HFE'' gene is located on short arm of chromosome 6 at location 6p22.2
Function
The protein ...
. It is most common among those of Northern European ancestry, in particular those of Celt
The Celts (, see pronunciation for different usages) or Celtic peoples () are. "CELTS location: Greater Europe time period: Second millennium B.C.E. to present ancestry: Celtic a collection of Indo-European peoples. "The Celts, an ancient ...
ic descent. The disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not express signs or symptoms of the condition. In this situation, the otherwise unaffected parents are referred to as carriers.
Signs and symptoms
Haemochromatosis is protean
In Greek mythology, Proteus (; Ancient Greek: Πρωτεύς, ''Prōteus'') is an early prophetic sea-god or god of rivers and oceanic bodies of water, one of several deities whom Homer calls the "Old Man of the Sea" ''(hálios gérôn)''. ...
in its manifestations, ''i.e.'', often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon, and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they have premature morbidity, if they are diagnosed early, but, more often than not, the condition is diagnosed only at autopsy.
Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.
The more common clinical manifestations include:
* Fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
* Malaise
As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century.
The term is often used ...
* Joint pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
(mainly knee and hand)
* Abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...
* Bronze or gray skin color (for this the illness was named "bronze diabetes" when it was first described by Armand Trousseau
Armand Trousseau (14 October 1801 – 23 June 1867) was a French internist. His contributions to medicine include Trousseau sign of malignancy, Trousseau sign of latent tetany, Trousseau–Lallemand bodies (an archaic synonym for Bence Jones ...
in 1865)
* Liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
fibrosis or cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
(with an increased risk of hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
): Liver disease is always preceded by evidence of liver dysfunction, including elevated serum enzymes specific to the liver, clubbing of the fingers, leuconychia, asterixis, hepatomegaly
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
, palmar erythema
Palmar erythema is reddening of the palms at the thenar and hypothenar eminences.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .
Causes
It is associated with va ...
, and spider naevi. Cirrhosis can also present with jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
(yellowing of the skin) and ascites.
* Diabetes mellitus type 2
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
: HH patients have insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
for liver disease, and poor insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
secretion due to pancreatic damage from iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
deposition.
* Erectile dysfunction
Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
and hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
, resulting in decreased libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
, amenorrhea
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...
* Congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, abnormal heart rhythms, or pericarditis
Pericarditis is inflammation of the pericardium, the fibrous sac surrounding the heart. Symptoms typically include sudden onset of sharp chest pain, which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sit ...
* Arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
of the hands (especially the second and third metacarpophalangeal joint
The metacarpophalangeal joints (MCP) are situated between the metacarpal bones and the proximal phalanges of the fingers. These joints are of the condyloid kind, formed by the reception of the rounded heads of the metacarpal bones into shallow cav ...
s), but also the knee
In humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the hu ...
and shoulder
The human shoulder is made up of three bones: the clavicle (collarbone), the scapula (shoulder blade), and the humerus (upper arm bone) as well as associated muscles, ligaments and tendons. The articulations between the bones of the shoulder mak ...
joint
A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw ...
s
* Weight loss
Less common findings including:
* Memory loss
Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use o ...
* Hair loss
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarri ...
* Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulating ...
* adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androge ...
* Deafness
Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is written ...
* Dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
s, including Parkinsonian
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
symptoms
* Dysfunction of certain endocrine organs
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
:
** Parathyroid gland
Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes pa ...
(leading to hypocalcaemia
Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol ...
)
** Pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
: secondary hypothyroidism
Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
, secondary hypogonadism
Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
** Adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
* An increased susceptibility to certain infectious disease
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
s caused by siderophilic microorganisms:
** ''Vibrio vulnificus
''Vibrio vulnificus'' is a species of Gram-negative, motile, curved rod-shaped (bacillus), pathogenic bacteria of the genus ''Vibrio''. Present in marine environments such as estuaries, brackish ponds, or coastal areas, ''V. vulnificus'' is relat ...
'' infections from eating seafood
Seafood is any form of sea life regarded as food by humans, prominently including fish and shellfish. Shellfish include various species of molluscs (e.g. bivalve molluscs such as clams, oysters and mussels, and cephalopods such as octopus an ...
or wound infection
** ''Listeria monocytogenes
''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the host' ...
''
** ''Yersinia enterocolica
''Yersinia enterocolitica'' is a Gram-negative, bacillus-shaped bacterium, belonging to the family Yersiniaceae. It is motile at temperatures of 22–29° C (72–84 °F), but becomes nonmotile at normal human body temperature. ''Y. enterocolitic ...
''
** ''Salmonella enterica
''Salmonella enterica'' (formerly ''Salmonella choleraesuis'') is a rod-headed, flagellate, facultative anaerobic, Gram-negative bacterium and a species of the genus ''Salmonella''. A number of its serovars are serious human pathogens.
Epidemi ...
'' (serotype Typhymurium)
** ''Klebsiella pneumoniae
''Klebsiella pneumoniae'' is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.
Although found in the normal flora of the mouth ...
''
** ''Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
''
** ''Rhizopus arrhizus
''Rhizopus arrhizus'' is a fungus of the family Mucoraceae, characterized by sporangiophores that arise from nodes at the point where the rhizoids are formed and by a hemispherical columella. It is the most common cause of mucormycosis in humans ...
''
** ''Mucor
''Mucor'' is a microbial genus of approximately 40 species of molds in the family Mucoraceae. Species are commonly found in soil, digestive systems, plant surfaces, some cheeses like Tomme de Savoie, rotten vegetable matter and iron oxide re ...
'' species
** ''Aspergillus fumigatus
''Aspergillus fumigatus'' is a species of fungus in the genus ''Aspergillus'', and is one of the most common ''Aspergillus'' species to cause disease in individuals with an immunodeficiency.
''Aspergillus fumigatus'', a saprotroph widespread in ...
''
** Cytomegalovirus
''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...
** Hepatitis B virus
''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus ''Orthohepadnavirus'' and a member of the ''Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B.
Disease
Despite there bein ...
** Hepatitis C virus
The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepato ...
In the hereditary hemochromatosis (HH or HHC), males are usually diagnosed after their forties and fifties, and women some decades later, during menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
. The severity of clinical disease varies considerably. Some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease have worse liver disease than those with either condition alone. Also, juvenile form of primary haemochromatosis (Hemochromatosis type 2) present in childhood with the same consequences of iron overload.
End-organ damage
Iron is stored in the liver, pancreas and heart.
Long-term effects of haemochromatosis on these organs can be serious, even fatal when untreated.
Since the liver is a primary storage area for iron and naturally accumulates excess iron over time, it is likely to be damaged by iron overload.
Toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy
Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stages ...
.
Together, they can increase the risk of liver cancer to one in three persons.
If excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, including (potentially fatal) congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
. The condition may be reversible when haemochromatosis is treated and excess iron stores are reduced. Arrhythmia
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
or abnormal heart rhythm can cause heart palpitations, chest pain, and light-headedness, and is occasionally life-threatening. This condition can often be reversed with treatment.
The pancreas, which also stores iron, is very important in the body's mechanisms for sugar metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
. Diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
affects the way the body uses blood sugar (glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
), and diabetes is, in turn, the leading cause of new blindness in adults and may be involved in kidney failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
.
Haemochromatosis may lead to cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
and its complications, including bleeding from dilated veins in the esophagus
The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
(esophageal varices
Esophageal varices are extremely dilated sub-mucosal veins in the lower third of the esophagus. They are most often a consequence of portal hypertension, commonly due to cirrhosis. People with esophageal varices have a strong tendency to develop ...
) and stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
(gastric varices
Gastric varices are dilated submucosal veins in the lining of the stomach, which can be a life-threatening cause of bleeding in the upper gastrointestinal tract. They are most commonly found in patients with portal hypertension, or elevated pr ...
) and severe fluid retention in the abdomen
The abdomen (colloquially called the belly, tummy, midriff, tucky or stomach) is the part of the body between the thorax (chest) and pelvis, in humans and in other vertebrates. The abdomen is the front part of the abdominal segment of the torso. ...
(ascites
Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, ab ...
).
Severity of periodontal disease
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
is associated with high transferrin saturation Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value te ...
in haemochromatosis patients.
Genetics
The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for hereditary haemochromatosis is ''HFE'' on chromosome 6
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...
, which codes for hepcidin, a protein that participates in the regulation of iron absorption. The ''HFE'' gene has three often observed genetic variants:
* rs1799945, c.187C>G, p.His63Asp (H63D);
* rs1800562, c.845G>A, p. Cys282Tyr (C282Y);
* rs1800730, c.193A>T, p.Ser65Cys (S65C).
The worldwide prevalence rates for H63D, C282Y and S65C (minor allele frequencies) are 10%, 3% and 1% respectively.
The C282Y allele is a transition point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
from guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
to adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
at nucleotide 845 in ''HFE'', resulting in a missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
that replaces the cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residue at position 282 with a tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
amino acid. Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body. Homozygosity
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for the C282Y genetic variant is the most common genotype responsible for clinical iron accumulation, though heterozygosity
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for C282Y/H63D variants, so-called compound heterozygotes In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it ...
, results in clinically evident iron overload. Considerable debate exists regarding the penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes. Most males homozygous for ''HFE'' C282Y show at least one manifestation of iron-storage disease by middle age. Individuals with the relevant genetic variants may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage.
The H63D variant is just a gene polymorphism
A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to gen ...
, and if there are no other changes, it may not have clinical significance. In a 2014 study, H63D homozygosity was associated with an elevated mean ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
level, but only 6.7% had documented iron overload at follow-up. As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload. Besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous H63D variant is significantly higher in elite endurance athletes comparing to ethnically matched controls, and is associated with high V̇O2max in male athletes.
.
Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease.[ Penetrance differs between populations.
Disease-causing genetic variants of the ''HFE'' ]gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
account for 90% of the cases of non-transfusion iron overload.
This gene is closely linked to the HLA-A3
HLA-A3 (A3) is a human leukocyte antigen '' serotype'' within HLA-A serotype group. The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. For A3, the alpha, "A", chain are encoded by the HLA-A allele group and ...
locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
.
Pathophysiology
Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the ''HFE'' gene, where a mutation puts the intestinal absorption of iron into overdrive. Normally, ''HFE'' facilitates the binding of transferrin
Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encode ...
, which is iron's carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, ''HFE'' is only part of the story, since many patients with mutated ''HFE'' do not manifest clinical iron overload, and some patients with iron overload have a normal ''HFE'' genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
. A possible explanation is the fact that ''HFE'' normally plays a role in the production of hepcidin
Hepcidin is a protein that in humans is encoded by the ''HAMP'' gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.
During conditions in which the hepcidin level is abnormally high, such as inflammation, se ...
in the liver, a function that is impaired in ''HFE'' mutations.
People with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus, the iron stores of the body increase. As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin
Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderin
Hemosiderin or haemosiderin is an iron-storage complex that is composed of partially digested ferritin and lysosomes. The breakdown of heme gives rise ...
and this is toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
to tissue, probably at least partially by inducing oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. Iron is a pro-oxidant Pro-oxidants are chemicals that induce oxidative stress, either by generating reactive oxygen species or by inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example an overdose of th ...
. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease
Wilson's disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, ...
, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs
The Dalmatian is a breed of dog, which has a white coat marked with black or brown-colored spots. Originating as a hunting dog, it was also used as a carriage dog in its early days. The origins of this breed can be traced back to present-day ...
. The latter also experience "bronzing".
Diagnosis
The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value te ...
or elevated serum ferritin.. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.
Blood tests
Serum ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
and fasting transferrin saturation Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value te ...
are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood. Measuring ferritin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250 ug/L in males and 200 ug/L in females are recognized as a threshold for further evaluation of haemochromatosis. Other source says that the normal values for males are 12-300 ng/mL and for female, 12-150 ng/mL. Fasting transferrin saturation is a better test to detect HH. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene
Human homeostatic iron regulator protein, also known as the HFE protein (High FE2+), is a protein which in humans is encoded by the ''HFE'' gene. The ''HFE'' gene is located on short arm of chromosome 6 at location 6p22.2
Function
The protein ...
.
Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues. Measuring ferritin provides a crude estimate of whole-body iron stores, though many conditions, particularly inflammatory conditions, infection, chronic alcohol consumption (mainly >20g/day), liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the sig ...
, cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, porphyria
Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ra ...
, Hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis (British spelling), and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a ...
, hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism ...
, obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
, metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
, diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, several blood transfusions, too many iron supplements, aceruloplasminemia
Aceruloplasminemia is a rare autosomal recessive disorder in which the liver can not synthesize the protein ceruloplasmin properly, which is needed to transport copper around the blood. Copper deficiency in the brain results in neurological proble ...
, atransferrinemia
Atransferrinemia is an autosomal recessive metabolic disorder in which there is an absence of transferrin, a plasma protein that transports iron through the blood.
Atransferrinemia is characterized by anemia and hemosiderosis in the heart and ...
, hyperferritinemia cataract syndrome and others, can elevate serum ferritin, which can account for up to 90% of cases where elevated levels are observed. Measuring iron in the body Serum ferritin in excess of 1000 ng/mL of blood is almost always attributable to haemochromatosis.
Other blood tests routinely performed include blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and pla ...
, renal function
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid ...
, liver enzyme
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...
s, electrolyte
An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
s, and glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
(and/or an oral glucose tolerance test
The glucose tolerance test (GTT, not to be confused with GGT test) is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, ...
).
Liver biopsy
Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, is measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis, but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding, and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable.[
]
MRI
MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.
Other imaging
Clinically, the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity in MRI scans
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
. Haemochromatosis arthropathy
An arthropathy is a disease of a joint. Types
Arthritis is a form of arthropathy that involves inflammation of one or more joints, while the term arthropathy may be used regardless of whether there is inflammation or not.
Joint diseases can be cla ...
includes degenerative osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
and chondrocalcinosis
Chondrocalcinosis or cartilage calcification is calcification (accumulation of calcium salts) in hyaline cartilage and/or fibrocartilage.Rothschild, Bruce M It can be seen on radiography.
Causes
Buildup of calcium phosphate in the ankle joints h ...
. The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand. The arthropathy can, therefore, be an early clue as to the diagnosis of haemochromatosis.
Functional testing
Based on the history, a physician might consider specific tests to monitor organ dysfunction, such as an echocardiogram
An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart.
It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound.
Echocardiography has become routinely used in th ...
for heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, or blood glucose monitoring for patients with haemochromatosis diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
.
Stages
The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):
# Genetic susceptibility but no iron overload. Individuals who have the genetic disorder only.
# Iron overload but no organ or tissue damage.
# Organ or tissue damage as a result of iron deposition.
Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.
Differential diagnosis
Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis type 1 is diagnosed.
* Haemochromatosis type 2.
* Haemochromatosis type 3
Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern. The first confirmed case was diagnosed in 1865 by French doctor Trousseau. ...
.
* Haemochromatosis type 4
Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people ...
.
* Haemochromatosis type 5.[
* ]African iron overload
African iron overload, also known as Bantu siderosis or dietary iron overload, is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa.
Dietary iron overload is the consumption of large amo ...
, formerly known as Bantu siderosis, was first observed among people of African
African or Africans may refer to:
* Anything from or pertaining to the continent of Africa:
** People who are native to Africa, descendants of natives of Africa, or individuals who trace their ancestry to indigenous inhabitants of Africa
*** Ethn ...
descent in Southern Africa
Southern Africa is the southernmost subregion of the African continent, south of the Congo and Tanzania. The physical location is the large part of Africa to the south of the extensive Congo River basin. Southern Africa is home to a number of ...
. Originally, this was blamed on ungalvanised barrels used to store home-made beer
Beer is one of the oldest and the most widely consumed type of alcoholic drink in the world, and the third most popular drink overall after water and tea. It is produced by the brewing and fermentation of starches, mainly derived from ce ...
, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get iron overload syndrome, and that a similar syndrome occurred in people of African
African or Africans may refer to:
* Anything from or pertaining to the continent of Africa:
** People who are native to Africa, descendants of natives of Africa, or individuals who trace their ancestry to indigenous inhabitants of Africa
*** Ethn ...
descent who have had no contact with this kind of beer (''e.g.,'' African Americans
African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of ens ...
). This led investigators to the discovery of a gene polymorphism in the gene for ferroportin
Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the ''SLC40A1'' gene, and is part of the Ferroportin (Fpn) FamilyTC# 2.A.100. Ferroportin i ...
, which predisposes some people of African descent to iron overload.
* Secondary haemochromatosis: its main cause is the Transfusional haemosiderosis. It is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s (such as those with thalassaemia
Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
). Other causes are: chronic hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
, chronic liver disease (hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
, hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
, cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
, fatty liver disease
Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complicat ...
), dysmetabolic hyperferritinemia, overdose of oral iron pills or iron injections, long-time kidney dialysis
Kidney dialysis (from Greek , , 'dissolution'; from , , 'through', and , , 'loosening or splitting') is the process of removing excess water, solutes, and toxins from the blood in people whose kidneys can no longer perform these functions natura ...
, and dyserythropoeisis, also known as myelodysplastic syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
. It is a disorder in the production of red blood cells that leads to increased iron recycling from the bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
and accumulation in the liver.
* Aceruloplasminemia
Aceruloplasminemia is a rare autosomal recessive disorder in which the liver can not synthesize the protein ceruloplasmin properly, which is needed to transport copper around the blood. Copper deficiency in the brain results in neurological proble ...
.
* Atransferrinemia
Atransferrinemia is an autosomal recessive metabolic disorder in which there is an absence of transferrin, a plasma protein that transports iron through the blood.
Atransferrinemia is characterized by anemia and hemosiderosis in the heart and ...
.
* Neonatal hemochromatosis
Neonatal Hemochromatosis is a rare and severe liver disease of unknown origin, though research suggests that it may be alloimmune condition. Its characteristics are similar to hereditary hemochromatosis, where iron deposition causes damage to the ...
* GRACILE syndrome
GRACILE syndrome is a very rare lethal autosomal recessive genetic disorder, one of the Finnish heritage diseases. GRACILE syndrome has also been found in the UK and Sweden, but not nearly as much as in Finland. It is caused by a mutation in the '' ...
* Porphyria cutanea tarda
Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fift ...
Screening
Standard diagnostic measures for haemochromatosis, transferrin saturation Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value te ...
and ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
tests, are not a part of routine medical testing. Screening
Screening may refer to:
* Screening cultures, a type a medical test that is done to find an infection
* Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees)
* Screening (environmental), a ...
for haemochromatosis is recommended if the patient has a parent, child, or sibling with the disease.
Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force
The United States Preventive Services Task Force (USPSTF) is "an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services". ...
, among other groups, which recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than one in 1,000. Although strong evidence shows that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy
Phlebotomy is the process of making a puncture in a vein, usually in the arm, with a cannula for the purpose of drawing blood. The procedure itself is known as a venipuncture, which is also used for intravenous therapy. A person who performs a p ...
) provides any clinical benefit. Recently, patients are suggested to be screened for iron overload using serum ferritin as a marker. If serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.
Treatment
Phlebotomy
Phlebotomy is the process of making a puncture in a vein, usually in the arm, with a cannula for the purpose of drawing blood. The procedure itself is known as a venipuncture, which is also used for intravenous therapy. A person who performs a p ...
Early diagnosis is vital, as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donation
A blood donation occurs when a person voluntarily has blood drawn and used for blood transfusion, transfusions and/or made into biopharmaceutical medications by a process called Blood fractionation, fractionation (separation of whole blood com ...
s.
Phlebotomy (or bloodletting
Bloodletting (or blood-letting) is the withdrawal of blood from a patient to prevent or cure illness and disease. Bloodletting, whether by a physician or by leeches, was based on an ancient system of medicine in which blood and other bodily flu ...
) is usually done at a weekly or each two weeks interval until ferritin levels are 50 μg/L or less. To prevent iron reaccumulation, subsequent phlebotomies are normally carried out about once every three to four months for males, and twice a year for females to keep the serum ferritin between 50 and 100 ug/L
Iron
chelation therapy
Chelation therapy is a medical procedure that involves the administration of Chelation, chelating agents to remove heavy metals from the body. Chelation therapy has a long history of use in clinical toxicology and remains in use for some very sp ...
Where venesection is not possible, long-term administration of an iron chelator
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...
as Deferoxamine
Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an un ...
(or Desferrioxamine), Deferasirox
Deferasirox, sold under the brand name Exjade & Asunra (in injectable form) & Oleptiss (Tablet formulation) both by Novartis among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving l ...
and Deferiprone
Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and h ...
is useful. Deferoxamine is an iron-chelating compound, and excretion induced by deferoxamine is enhanced by administration of vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.
Organ damage
* Treatment of organ damage (heart failure with diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
s and ACE inhibitor
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
therapy). Hepatic transplantation
Liver transplantation or hepatic transplantation is the replacement of a Liver disease, diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for Cirrhosis, end-stage liver disease and ...
in patients with liver failure.
Diet
* Limiting intake of alcoholic beverage
An alcoholic beverage (also called an alcoholic drink, adult beverage, or a drink) is a drink that contains ethanol, a type of alcohol that acts as a drug and is produced by fermentation of grains, fruits, or other sources of sugar. The c ...
s, vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
(increases iron absorption in the gut), red meat
Meat is animal flesh that is eaten as food. Humans have hunted, farmed, and scavenged animals for meat since prehistoric times. The establishment of settlements in the Neolithic Revolution allowed the domestication of animals such as chic ...
(high in iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
), and potential causes of food poisoning
Foodborne illness (also foodborne disease and food poisoning) is any illness resulting from the spoilage of contaminated food by pathogenic bacteria, viruses, or parasites that contaminate food,
as well as prions (the agents of mad cow disease) ...
(shellfish
Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater envir ...
, raw seafood
Seafood is any form of sea life regarded as food by humans, prominently including fish and shellfish. Shellfish include various species of molluscs (e.g. bivalve molluscs such as clams, oysters and mussels, and cephalopods such as octopus an ...
)
* Increasing intake of substances that inhibit iron absorption, such as high-tannin
Tannins (or tannoids) are a class of astringent, polyphenolic biomolecules that bind to and precipitate proteins and various other organic compounds including amino acids and alkaloids.
The term ''tannin'' (from Anglo-Norman ''tanner'', ...
tea
Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of '' Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of southwestern China and northe ...
, calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
, and foods containing oxalic and phytic acid
Phytic acid is a six-fold dihydrogenphosphate ester of inositol (specifically, of the ''myo'' isomer), also called inositol hexakisphosphate (IP6) or inositol polyphosphate. At physiological pH, the phosphates are partially ionized, resulting ...
s (such as collard greens
Collard is a group of certain loose-leafed cultivars of ''Brassica oleracea'', the same species as many common vegetables including cabbage ( Capitata group) and broccoli ( Italica group). Collard is a member of the Viridis group of ''Brassica ...
, which must be consumed at the same time as the iron-containing foods to be effective)
Chelating polymers
A novel experimental approach to the hereditary haemochromatosis treatment is the maintenance therapy with polymeric chelators. These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT
Git () is a distributed version control system: tracking changes in any set of files, usually used for coordinating work among programmers collaboratively developing source code during software development. Its goals include speed, data in ...
and thus limiting the uptake of these ions and their long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, such an approach has virtually no side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
in sub-chronic studies. Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.
Prognosis
Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not. Patients without liver disease or diabetes had similar survival rate to the general population.
Epidemiology
Haemochromatosis is one of the most common heritable genetic conditions in people of Northern Europe
The northern region of Europe has several definitions. A restrictive definition may describe Northern Europe as being roughly north of the southern coast of the Baltic Sea, which is about 54th parallel north, 54°N, or may be based on other g ...
, with a prevalence of 1:200. The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism. In the U.S.
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
, the frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Whereas, the worldwide frequency of the C282Y and H63D mutations is about 1.9% and 8.1%, respectively, so mutation in H63D allele are more than C282Y allele. The prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
of mutations in iron-metabolism genes varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
carriers of an HFE mutation, 0.5% were homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for an ''HFE'' mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for ''HFE'' mutations do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S.
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
with a prevalence of 1:300 in the non-Hispanic white population, It is 2-3 times most common in males.
Genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian friar wor ...
studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
may have provided an evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
ary advantage by maintaining higher iron levels in the blood.
The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3
Haemochromatosis type 3 is a type of iron overload disorder associated with deficiencies in transferrin receptor 2. It exhibits an autosomal recessive inheritance pattern. The first confirmed case was diagnosed in 1865 by French doctor Trousseau. ...
, Haemochromatosis type 4
Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people ...
and Haemochromatosis type 5, were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin
Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosi ...
protein, is widely distributed in central Europe and Greece.
Terminology
The term "haemochromatosis" is used by different sources in many different ways.
It is often used to imply an association with the ''HFE'' gene. For many years, ''HFE'' was the only known gene associated with haemochromatosis, and the term "hereditary haemochromatosis" was used to describe haemochromatosis type 1. However, many different genetic associations with this condition are now known. The older the text, or the more general the audience, the more likely that ''HFE'' is implied. "Haemochromatosis" has also been used in contexts where a genetic cause for iron accumulation had not been known. In some cases, however, a condition that was thought to be due to diet or environment was later linked to a genetic polymorphism, as in African iron overload.
History
In 1847, Virchow described a golden brown granular pigment that was soluble in sulfuric acid and produced red ash on ignition. The disease was first described in 1865 by Armand Trousseau
Armand Trousseau (14 October 1801 – 23 June 1867) was a French internist. His contributions to medicine include Trousseau sign of malignancy, Trousseau sign of latent tetany, Trousseau–Lallemand bodies (an archaic synonym for Bence Jones ...
in a report on diabetes in patients presenting with a bronze pigmentation of their skin. Two years later, Perls developed the first practical method for the analysis of iron in tissue. Despite Trousseau did not associate diabetes with iron accumulation, the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen
Friedrich Daniel von Recklinghausen (; December 2, 1833 – August 26, 1910) was a German pathologist born in Gütersloh, Westphalia. He was the father of physiologist Heinrich von Recklinghausen (1867–1942).
Early life
Recklinghausen was b ...
in 1890. In 1935, English gerontologist Joseph Sheldon described the cases of haemochromatosis. He established this as the name of the disorder and his detailed monograph. Despite lacking the modern molecular techniques accessible today, he came to accurate conclusions that describe haemochromatosis disease as an inborn error of metabolism where this inherited disorder can increase the absorption of iron and thus cause tissue damage due to iron deposition. Moreover, he rejected theories that alcohol, drug, and other factors contribute to the disorder.
The clinical case series from 1935 to 1955 indicated that haemochromatosis was more common than had been acknowledged. During the 1960s, MacDonald, a pathologist at Boston City Hospital, diverted attention away from the true cause of haemochromatosis. He believed that haemochromatosis was a nutritional condition because he observed many drunken patients of Irish ancestry. During this period of time, other investigators reported additional evidence suggesting that a genetic factor could play a central role in the absorption of iron in people with haemochromatosis. However, alcohol consumption is known to increase the risk of liver injury in haemochromatosis. This finding is consistent with the concept that excess iron metabolism is a primary cause of haemochromatosis disease.
Finally, in 1976, Marcel Simon and his collaborators confirmed that haemochromatosis is an autosomal recessive disorder that has a link to the human leukocyte antigen (HLA) region of the genome. It took 20 years for researchers at Mercator Genetics to effectively identify and clone the haemochromatosis genes using a positional cloning approach.
In 1996, Feder et al. identified HFE, which is a major histocompatibility complex (MHC) gene. They found that 83% of patients have homozygosity for a missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
(C282Y) in the HFE gene. Finally, several groups reported their findings in a series of patients with haemmochromatosis where they discovered the existence of the C282Y mutation in about 85-90% of the cases. The discovery has led to improved clinical medicine and liver disease evaluation.
References
External links
GeneReview/NIH/UW entry on HFE-Associated Hereditary Hemochromatosis
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{{DEFAULTSORT:Hfe Hereditary Hemochromatosis
Iron metabolism
Genetic diseases and disorders
Red blood cell disorders
Hepatology
Arthritis
Disturbances of human pigmentation
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