Skin is metallic or slate grey

Introduction Skin pigmentation occurs in hemochromatosis: 90% to 100% of patients have skin pigmentation. The characteristic metallic color or slate gray is sometimes described as bronze or dark brown, due to increased melanin (causing bronze) and iron deposits (causing gray pigment) to sink in the dermis. HHC is characterized by excessive iron (ferritin, hemosasine) deposited in the parenchyma of many organs, especially in the liver, heart, endocrine glands; pancreas, gastrointestinal tract, spleen, lungs, joints and blood vessel walls There are varying degrees of iron deposition at all places.

Cause

(1) Causes of the disease

Since Trousseau first reported a case of hemochromatosis in 1865, it was thought that the disease was caused by excessive drinking or eating and other external factors. Later, the HLA type was tested and statistically proven to be closely related to the short arm HLA class complex on chromosome 6. Mainly HLA-A3-B14, HLA-A3-B7, the frequency is significantly higher than normal people. In 1989, HLA-A2 and A11 were found to be the second common allele. HLA-A1-B3 and HLA- have also been reported. The A3-B15 abnormal gene was confirmed to be an autosomal recessive hereditary disease by family survey and HLA type investigation. In the same family, the h (hemochromatosis) allele of HLA and the HLA-H site antigen are transmitted to each other to form a homozygote or a heterozygote. Any haplotype (Hh) with abnormal h is heterozygous; there is no abnormal haplotype, and two normal haplotypes (HH) are normal. Inherited according to the Mendelian autosomal recessive inheritance model.

In recent years, all human chromosome patterns have been clarified. Many scholars have sequenced the small satellite DNA marker on the short arm of chromosome 6, Southern blot, family analysis, etc., and found that the hemochromatosis gene is very close to D6S105 (Jazwinska et al., 1993). D6S105 is approximately 2 cm away from HLA-A (Centi Morgan, PCT) and is highly correlated with hemochromatosis. In 1996, Feder et al. confirmed by gene sequencing and crystal protein analysis that the disease is due to mutation of HPE gene. The most common is that the 845th nucleoside GA makes the 282th amino acid part of cystinetyrosine 845A ( Or C282Y, C stands for cystine, Y stands for tyrosine); another common mutation is amino acid histidine at the 63rd position of the 187th nucleoside CGaspartic acid 187G; H63D(H Represents histidine, D stands for aspartic acid), and the third HFE gene mutation is serine Scystine C at the 65th site of 193T (S65C), and there are other reports of a special type of HFE mutant gene.

It has been proven in the world that C282Y is the main genetic mutation type of this disease, and the proband is about 80% to 90% homozygous (about 90% in the UK, 83% in North America), and 21% in the non-C282Y gene mutation. ~43% is H63DC282Y/H63D composite, accounting for 7%. Mura et al. detected 711 cases of probands with C282Y accounting for 86.8% and H63D accounting for 75%. It was also reported that S65C accounted for 7.8%, the latter mostly being light patients.

(two) pathogenesis

The pathogenesis of HHC is still unclear, and more studies are related to HFE-related HHC. The pathophysiological mechanisms of HFE-associated HHC include: genetic defects in HHC; increased plasma iron ions; iron ions cause tissue damage.

Genetic factor

There are four HHC pathogenic genes that have been discovered, and the HFE gene is more studied. 83% of the classic HHC cases in the United States are related to the cysteine tyrosine substitution (C282Y) of HFE protein 282 (GA). ). The mutation can be found in 85% to 100% of HHC patients in the Nordic population, but only in 60% of patients in the Mediterranean population (such as southern Italy). There is a second mutation at position 63, histidine-aspartate (H63D), but this does not appear to cause excessive iron loading, except for individuals with heterozygous H63D and heterozygous C282Y (complex heterozygosity). A rare mutation is the mutation at position 65, cysteine serine (S65C); heterozygotes formed with H63D or C282Y are rare and controversial. Adolescent HHC is caused by hemojuvelin and HAMP genes; TfR2-related HHC is caused by TfR2.

2. Increased iron content

In vivo iron is divided into functional state iron and stored iron: functional state iron includes hemoglobin iron (more than 2/3 of iron in the body), myoglobin iron (10% to 15% iron), transferrin (3 to 4 mg), Enzymes and cofactors, etc.; storage of iron includes ferritin and hemosiderin. The metabolic balance of iron is mainly regulated by the absorption of iron by the duodenum. Usually, the food contains 10-15 mg of iron per day, and the absorption and loss of iron in the small intestinal mucosa are balanced; in the equilibrium state, 1-2 mg is absorbed and lost every day; the amount of iron absorption in the intestinal mucosa of HHC patients is 3-6 mg/day or more. The body can not use or exclude too much iron, exceeding the body's need; the amount of iron in normal human body is 3 ~ 5g; the total amount of iron in HHC body is generally more than 15 ~ 40g, up to 50g or more, HHC multi-absorbed iron lg /year, so it takes more than 30 years to gather 20 to 40g of iron. With the increase of age, iron deposition increases, plasma iron concentration increases, and then the liver iron concentration increases, tissue damage, and finally cause organ damage. The mechanism by which disease-causing genes cause excessive iron overload is not fully understood. The mechanism by which excessive iron deposition leads to tissue damage has the following points:

(1) Iron atoms can destroy the stability of the cell lysosomal membrane, causing the hydrolase therein to enter the cytosol and cause cell destruction (the lysosome full of iron is broken).

(2) Excess iron atoms in the cells can be oxidized to form excessive fat-soluble ferrite, which can increase the activity of high-activity oxygen free radicals and lipids. The latter two substances can damage mitochondria, microsomes and Cell membrane, protein, DNA, etc., cause cell damage and death.

(3) Iron atoms can directly stimulate the synthesis of collagen fibers between tissue cells, leading to organ fibrosis, and activated astrocytes stimulate collagen synthesis.

Whether HHC is still affected by menstruation, pregnancy, blood donation, gastrointestinal bleeding, alcohol, etc. More important are eating habits and alcoholism. For a long-term intake of iron-rich diets, alcohol and meat-based people, the incidence of HC is significantly higher than that of low-iron diets and vegetarians.

an examination

Related inspection

Blood routine blood sugar

Clinical manifestation

With the prolongation of time and the accumulation of iron, HHC patients gradually develop symptoms and become more severe. HHC is usually asymptomatic or has no specificity in the initial symptoms, including weakness, joint pain, lethargy, chronic fatigue, weight loss (wasting), abdominal pain, skin color changes, lack of libido, and the like. The three most important clinical manifestations of advanced disease are cutaneous iron pigmentation, secondary diabetes, and cirrhosis.

HFE-related HHC, male clinical manifestations usually become obvious in 40 to 50 years old; female patients often have symptoms after menopause, and the onset age is often later than men. HHC and HFE-related HHC have a common clinical feature due to non-HFE gene alteration. Adolescent HHC: typical in the 10 to 30 years old; common complications include: DM, hypogonadism, arrhythmia, heart failure, and heart failure more often than HFE-related HHC.

Differential diagnosis

Skin pigmentation: The color of the skin is determined by the melanin (brown), carotene (yellow), oxidized hemoglobin (red) in the dermal capillaries, and reduced hemoglobin (blue) in the vein. important. In addition to ethnic and individual differences in the color of the skin, normal people often have physiological pigmentation in the exposed parts, wrinkles and rubbed parts; therefore, the change of skin color should be compared with the skin around the patient and the affected part. It should not be judged solely from the depth of color.

Skin pigmentation is bronze: Loss of salt nephritis has typical clinical manifestations of polyuria and nocturia, skin pigmentation is bronze, etc., salt-losing nephritis, also known as Thorn syndrome, is currently considered to be a group with severe renal Loss of salt is a special type of certain kidney disease characterized by it.

Red complexion: The skin color of a person is determined by congenital factors such as race and heredity, and is closely related to the distribution of capillaries, the amount of pigment, and the thickness of subcutaneous fat. The normal person's skin color should be rosy and shiny. However, the blood circulation is not good, or there are problems in the heart, liver and intestines. Improper diet can make people's skin redness. The skin presents an abnormal reddish red color. When the weather is cold, the cheeks, especially the tip of the nose, will appear reddish.

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