Hemochromatosis

Introduction to hemochromatosis Hemochromatosis (HC), also known as hereditary hemochromatosis (HHC, HH), is a common chronic iron overload disease, an autosomal recessive disorder; due to inappropriate increase in intestinal iron absorption, Excess iron is stored in substantial cells such as the liver, heart and pancreas, leading to degenerative and diffuse fibrosis, metabolic and dysfunctional tissues. The main clinical features are skin pigmentation, cirrhosis, and secondary diabetes. basic knowledge The proportion of illness: 0.002% Susceptible people: no specific population Mode of infection: non-infectious Complications: cirrhosis, arrhythmia, peritonitis, diabetes

Cause of hemochromatosis

(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, after testing for HLA type, and statistically proven that the disease occurred with No. 6 The short-armed HLA class complexes on chromosomes are closely related, mainly HLA-A3-B14, HLA-A3-B7, which is significantly more frequent than normal. In 1989, HLA-A2 and A11 were found to be the second common allele. HLA-A1-B3 and HLA-A3-B15 abnormal genes have also been reported, which have been proved to be autosomal recessive hereditary diseases by family investigation and HLA type investigation.

Hg (hemochromatosis) alleles and HLA-H site antigens of HLA are transmitted in the same family to form homozygous or heterozygous, and any haplotype (Hh) of abnormal h is heterozygous; Abnormal haplotypes, two normal haplotypes (HH) are normal, inherited by the Mendelian autosomal recessive inheritance model.

In recent years, since all human chromosome patterns have been clarified, many scholars have sequenced small satellite DNA markers 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 about 2cm away from HLA-A (Centi Morgan, PCT), and is highly correlated with hemochromatosis. In 1996, Feder et al. through gene sequencing, crystal protein analysis confirmed that the disease is due to HPE gene mutation, the most common is in the first 845 nucleosides GA make cystine tyrosine at the 282th amino acid position 845A (or C282Y, C stands for cystine, Y stands for tyrosine); another common mutation is the 187th nucleus The amino acid histidine of the 63th part of the glycoside CGaspartic acid 187G; H63D (H stands for histidine, D stands for aspartic acid), and the third HFE gene mutation is 193T (S65C) 65th There are several other types of HFE mutant gene reports, such as serine Scystine C.

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 compound, accounting for 7%, Mura and other 711 cases have tested C282Y accounted for 86.8%, H63D accounted for 75%; S65C accounted for 7.8%, the latter mostly light patients.

(two) pathogenesis

The pathogenesis of hemochromatosis is mainly the genetic abnormality on the sixth pair of chromosomes, which leads to an increase in iron absorption in the small intestine mucosa, so that the iron content in the body increases, which is more than 5 to 10 times higher than normal. Tracer nuclides have shown that the rate of oral iron absorption in patients with hemochromatosis can be as high as 20% to 45% (normally 1.5% to 4.4%). There are three theories about the mechanism of liver deposition and liver cirrhosis caused by excessive iron deposition in the body: 1. The hemosiderin releases iron in the acidic environment of lysosome, which makes the lysosomal membrane unstable, and the hydrolase Entering the cytoplasm, causing damage; 2 excessive free iron causes lipid peroxidation of the lipids of the organelles, further destruction of the mitochondria and cell membrane, causing cell death; 3 excessive iron in the liver directly stimulates the synthesis of collagen fibers, resulting in Liver fibrosis and cirrhosis.

Hemochromatosis prevention

There is no specific method, should avoid alcohol and eat high-iron foods, in addition, should actively treat the primary disease, secondary diabetes, heart failure, cirrhosis, loss of libido, etc., should be treated accordingly.

Hemochromatosis complications Complications cirrhosis arrhythmia peritonitis diabetes

1. Late stage gastrointestinal bleeding due to esophageal varices, the incidence of hepatocellular carcinoma is 29%, this malignant complication only occurs in cases with cirrhosis, compared with other types of cirrhosis, the disease occurs There are many liver cancer patients. This liver cancer is often multi-centered nodular, rather than a single large mass, and there is not a large amount of alpha-fetoprotein released into the blood. If the liver biopsy is performed percutaneous, if it is a small point Liver cancer, the result may be negative.

2. Cardiac complications can occur suddenly within a few days of heart failure and/or arrhythmia, so those with evidence of cardiac involvement should be treated as an emergency, and alcoholics increase the risk of heart disease.

3. If acute and severe abdominal pain occurs, bloating and shock are often complicated by bacterial peritonitis, which is a serious fatal complication in this disease.

4. In addition to liver cancer, the disease can be complicated by other tumors and the second tumor is mostly advanced elderly patients. Other tumors include bladder cancer, ileal cancer, colon cancer, prostate cancer, etc. It has been reported that at least 7 years after removing excess iron A tumor appears.

5. Diabetes, joint disease is also the most common complication of this disease, appears in the course of the disease, should be actively given early treatment.

Hemochromatosis Symptoms Common symptoms Abdominal pain, weakness, hepatomegaly, peritonitis, dyspepsia, liver coma, testicular atrophy, liver function damage, weight loss, dry skin

Clinical manifestation

Patients with hemochromatosis develop clinical symptoms when the amount of iron stored in the body reaches 25 to 50 g. The average age at which symptoms appear is 50 years old, but early clinical manifestations due to hemochromatosis are often overlooked, and it usually takes 4 to 5 years to establish a diagnosis. The disease is more common in men, with a male to female ratio of 8:1.

The main symptoms of hemochromatosis are skin pigmentation, diabetes, cirrhosis and hypogonadism. Due to improvements in modern diagnostic methods, some homozygotes with no typical symptoms or even symptoms have not been found. Recently, analysis of 163 patients showed that 83% had weakness and lethargy, 58% had abdominal pain, 43% had joint pain, 38% had loss of libido and aging, and 15% had symptoms of heart failure. 69% had cirrhosis, 83% hepatomegaly, 13% splenomegaly, 20% body hair loss, 8% male breast development, 75% skin pigmentation, and 55% clinical diabetes.

First, the liver

Liver enlargement precedes cirrhosis, and its degree of swelling is related to the degree of iron deposition. 69% of patients with hemochromatosis and non-cirrhosis have hepatomegaly, and 90% of hepatic cirrhosis has hepatomegaly, suggesting that iron deposition itself is a cause of liver disease. main role. After the formation of cirrhosis, liver dysfunction and portal hypertension occur frequently. Liver function tests may have serum albumin decrease, prothrombin time prolonged, transaminase may increase slightly, and other non-specific manifestations of cirrhosis may have decreased libido and stagnation. , amenorrhea, male breast development.

The threshold of intrahepatic iron deposition leading to cirrhosis and liver fibrosis is 22 mg/g dry weight, which is prone to liver cancer on the basis of cirrhosis. The incidence of hepatic cirrhosis is 200 times higher than that of normal people, mainly primary. Most of hepatocellular carcinoma can originate from intrahepatic bile ducts, and the incidence of extrahepatic cancer is not high.

Most of the right upper quadrant pain is chronic, but sometimes it is acute, acute abdominal pain is very intense, and sometimes it can cause painful shock. The reason is not very clear.

Second, diabetes

In patients with hemochromatosis, 71% had dominant diabetes, 60% of which were insulin-dependent, 31% were non-insulin-dependent; 20% of patients with non-cirrhosis had clinical diabetes, 60% of whom were non-insulin-dependent. In other patients with hemochromatosis with non-dominant diabetes, 31% had impaired glucose tolerance. For patients with hemochromatosis who have been treated for long-term survival, complications such as retinopathy, neuropathy, kidney disease and peripheral vascular disease are similar to other diabetes.

Third, skin pigmentation

Almost all patients have skin pigmentation, especially in exposed areas, but because of the occlusion of progress, patients and their relatives often do not pay attention.

Fourth, the heart

One third of patients had arrhythmia, 15% of patients may have heart failure, ECG showed low voltage, T wave changes, premature beats, atrial and ventricular fibrillation, bundle branch block, echocardiography showed whole heart enlargement.

Five, joint lesions

The incidence rate is 43% to 57%, of which only 55% have joint pain symptoms, joint lesions can be seen, some joints are not painful, physical examination is normal, X-ray can be found to have lesions, such as cystic changes and joint edge hardening changes More common in the second and third metacarpophalangeal joints, knee and hip joints can also be affected. The incidence of joint lesions has nothing to do with cirrhosis, and can be the first or only manifestation.

6. Endocrine gland abnormalities

Male patients may have loss of libido and impotence, accompanied by secondary sexual changes, these changes are often associated with liver involvement, but more often before cirrhosis, female amenorrhea has no relationship with cirrhosis, the incidence of male breast development is low For patients with cirrhosis caused by other causes, and with or without cirrhosis, most patients with hypogonadism have low gonadotropin secretion, low progesterone, low follicle stimulating hormone and gonadotropin-releasing hormone response. low.

Generally, the pituitary-adrenal and pituitary-thyroid functions are normal.

Hemochromatosis check

Laboratory inspection

1. Peripheral blood: more normal late stage combined with severe cirrhosis can occur anemia, white blood cells and thrombocytopenia.

2. Serum iron (SI): morning fasting serum iron in normal humans 60 ~ 180g / dL (11 ~ 30mol / L), and HHC in 180 ~ 300g / d (32 ~ 54mol / L), elevated serum iron levels Also seen in patients with alcoholic liver disease, serum iron is not reliable for screening HHC without transferrin saturation, but can be used to detect the effect of bloodletting therapy.

3. Seritin: serum ferritin is 20-200 g/L (ng/ml) in normal males, 15-150 g/L (ng/ml) in normal females, and 300-3000 g in males: HHC patients. /L, female HHC patients are 250 ~ 3000g / L, serum ferritin elevation can also be seen in inflammatory infections, malignant tumors, hyperthyroidism, chronic liver disease, serum lutein levels increase by 1g / L reflects an increase in iron storage in the body of about 65mg.

4. Transferrin saturation transferrin saturation (unsaturated iron fertility, transferrin saturation) = serum iron / serum total iron binding capacity × 100%, is a sensitive, specific indicator of iron increase, early Biochemical abnormalities can be found, normal people are 20% to 35%, and HHC can reach 55% to 100%. The increase can also be seen in various necrotic inflammatory liver diseases (chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver). Some tumors, etc.

Combined serum ferritin and transferrin saturation assays are methods for detecting the sensitivity and specificity of HHC.

5. Liver tissue examination: The degree of hepatic fibrosis and cirrhosis can be observed, and the liver iron concentration can be determined by chemical method. This is a positive diagnostic method for the diagnosis of hemochromatosis. The staining of hemosiderin should be observed by Prussian blue staining. The conventional method of liver biopsy has a certain practical value in calculating the liver iron index.

Liver biopsy is the main diagnostic tool for histological examination to determine the nature of the lesion; it can also be used for histochemical estimation of liver iron content and determination of hepatic iron dry weight.

The determination of iron content in liver tissue showed that the iron content per milligram of dried liver tissue of HHC usually exceeds 180 pmol (normal liver should be less than 120 pmol), and the liver iron of patients with symptomatic HHC usually reaches 10,000 to 30,000 g/g (dry weight). (Normal: 300-1500 g/g, 5-27 mol/g dry weight), uncomplicated HHC, cirrhosis and fibrosis can be seen in iron over 20,000 g/g; when HHC is combined with alcoholic or viral liver disease, Cirrhosis and fibrosis occur when the concentration of iron ions is low; in the early stages of atypical or young patients, the liver iron content is less than 10000 g/g.

Prussian blue staining is used to detect iron content and distribution. Grade I and II Prussian blue staining can be found in normal liver, grade III Prussian blue staining can be seen by alcoholic liver disease; in the absence of other diseases, grade III and IV Prussian blue staining is seen in HHC.

Liver test to determine the iron concentration and calculate the hepatic iron index (HII), HII = (g / g dry weight) / (56 × age), or (mol / g dry weight) / age, when the liver iron was detected When the deposition and iron content increase (HII>1.9, the average person is usually less than 1 (1.5), the average liver iron concentration is >50 mol/g), the diagnosis can be confirmed, the false negative is rare, and the fatty liver can have a false negative.

6. Bone marrow smear or section: increased hemosiderin particles, such particles can also be seen in urine sediment, skin biopsy can be seen melanin and hemosiderin particles, about the majority of patients see epidermal basal cells and sweat glands have secondary Gray deposit of iron.

7. Glucose tolerance test: more abnormal blood sugar can be increased, transaminase is often increased, but liver function can also be normal, plasma luteinizing hormone, follicle stimulating hormone and testosterone are reduced.

8. Genetic testing With the advent of genetic testing, it is very common for HC to be diagnosed in asymptomatic individuals. The genetic tests that can be performed are C282Y, H63D, etc., for genotype clinical diagnosis and first-degree relative screening.

Film degree exam

1. X-ray examination: hand, wrist or other affected joints show soft tissue swelling, narrow joint space, articular surface irregularities and decreased bone density, osteoporosis and cortical cysts are also common, cartilage calcification and ligamental calcification around the joint are Late manifestations of arthropathy.

2. X-ray film chest examination: showing increased pulmonary vascular texture or pleural effusion, may have heart enlargement.

3. About 30% of cases have abnormal electrocardiogram, and there may be atrial or ventricular arrhythmia, premature contraction, supraventricular and ventricular tachycardia, ventricular fibrillation, low voltage or abnormal ST-T segment.

4. Cardiac ultrasound scan and cardiac catheterization can confirm restrictive cardiomyopathy.

5. Cardiac X-ray dynamic photography: It can show the reduction of ventricular contraction amplitude, which is a sensitive method to find out the heart involvement.

6. Liver computed tomography (CT) examination and magnetic resonance imaging examination: cases with excessive iron load can show increased liver density, increased tissue iron, increased sensitivity, and severe liver CT density of more than 36 CT units.

7. Deferoxamine test intramuscular chelating agent deferoxamine (de-iron sensitive) 500 ~ 1000mg (or 10mg / kg), collected 24h urine test iron content, normal people <2mg / 24h, muscle relief is very good, can Urinary iron excretion increased (>2mg/24h), HHC>10mg/24h.

This test is simple and easy, and it is helpful for diagnosis. However, the results of patients with renal dysfunction are unreliable. In some cases, when the diagnosis is difficult, this treatment can be used as a diagnostic test.

Diagnosis of hemochromatosis

diagnosis

When typical symptoms appear, diagnosis should be no difficulty, but should not wait for evidence of organ damage (such as arthritis, diabetes or cirrhosis) to make a diagnosis, these complications are difficult to reverse, early diagnosis for prevention Severe complications, especially prevention of liver cancer, are important. There is no effective method for early diagnosis. In the case of no secondary infection and complicated liver cancer, the simplest and most practical screening experiment is serum iron. (SI), serum ferritin, total iron binding capacity and transferrin saturation determination, SI greater than 32mol / L (180g / dl), transferrin saturation of 60% or higher, or a gradual increase trend, If other causes can be ruled out, it is highly probable that hemochromatosis is homozygous. Serum ferritin is also a useful screening test. Deferoxamine test is performed on suspected patients: deferoxamine is an iron chelator, intramuscular injection of iron. After the amine 10mg/kg, the normal human 24h urinary iron excretion generally does not exceed 2mg, and the patient usually exceeds 10mg. This test helps to indirectly peep the iron content in the parenchymal cells in the body, and also contributes to the clinical Off, the lack of reduction in the excretion of renal dysfunction and ascorbic acid (vitamin C).

Relatives of asymptomatic patients and patients with hemochromatosis, especially before the age of 30, often have no obvious symptoms and signs, but serum ferritin and transferrin saturation can be slightly increased, liver biopsy may have hemosiderin deposition, liver The iron concentration is less than 100 mol/g dry tissue weight, and the liver iron index is often greater than 1.9. If serum ferritin is normal, serum ferritin and transferrin saturation should be detected once a year in this group of cases.

The HLA test is only valuable if the patient's siblings confirm other asymptomatic patients with hemochromatosis. The brothers and sisters whose HLA genotype is consistent with the proband are homozygous for the disease. They should be checked every 2 to 3 years. A transferrin saturation and serum ferritin to determine when iron storage is too much for timely treatment, but HLA examination should not be used for screening in the general population, high cost and lack of specificity. Many people in the general population have HLA. A normal person with -A3 or HLA-B7 antigen, for example, HLA-A3 linked to h gene, about 71% of patients have the antigen, such as 4% of hemochromatosis, then 3 in the general population The sputum is homozygous for the disease with HLA-A3 antigen. The HLA-A3 owner in the general population is 28%, which means that if 1000 HLA-A3 are detected in the general population, 277 of them have the antigen. In normal people, only 3 patients are patients. In countries with extremely low incidence of this disease in China, HLA screening cannot be used for screening. Since the h-mutation gene of hemochromatosis is not completely clear, genetics and molecular biology tests cannot be used. Early diagnosis.

Differential diagnosis

The clinical manifestations of hereditary hemochromatosis can be misdiagnosed as diabetes, idiopathic cardiomyopathy, rheumatoid arthritis, degenerative arthritis, alcoholic cirrhosis, hypothyroidism and many other diseases, improving the tendency of hemochromatosis in such patients. Be alert and conduct screening tests for SI, serum ferritin and transferrin saturation. The differential diagnosis is not difficult. The disease should be differentiated from other causes of liver cirrhosis and diabetes, chronic adrenal insufficiency and melanosis. .

Skin pigmentation

(1) Patients with cirrhosis may have hyperpigmentation, hepatogenic diabetes, clinically similar to HC; but patients with cirrhosis often have hepatitis, malnutrition, schistosomiasis and other medical history, HC family history is negative, liver function damage is more obvious than HC, part The patient's hepatitis virus immunological examination can be positive, and the liver wear result is significantly different from HC.

(2) Chronic adrenal insufficiency often has obvious pigmentation, which is easy to be confused with HC. Especially in some patients, diabetes can be misdiagnosed as the disease, but chronic adrenal insufficiency usually has no liver damage and the heart is reduced. Adrenal cortical function tests show low, skin biopsy without iron deposition, so it can be identified.

(3) Patients with melanosis are common in middle-aged women, mainly with facial pigmentation. The cause is unknown. It may be related to sun exposure and cosmetic use. Except for pigmentation, no organ damage, iron deposition and iron metabolism. Abnormal laboratory findings.

2. Identification of diseases with excessive iron overload. The disease should be differentiated from diseases with excessive iron overload. Secondary iron overload is excessive, and iron is mainly deposited in Kupffer cells; however, severe iron When the load is too much, the primary and secondary are not easy to distinguish.

Its identification points:

(1) There are primary diseases such as aplastic anemia, iron anemia, anemia, and renal anemia.

(2) There is a long history of repeated blood transfusion, each blood transfusion of 500ml, about hemoglobin 65g / L per 100g / L hemoglobin iron 330mg, that is, iron 215mg was input, in patients with severe beta thalassemia or chronic aplastic anemia About 12 to 50 units of blood per year are infused, that is, about 2.5 to 11.0 g of iron is input per year, while normal people discharge about 1 mg of iron per day. If the iron load is excessive, the iron discharge can be increased by about 3 times, that is, An adult can discharge about 1.1g of iron per year, subtracting the amount of input from the input, and increasing the amount of iron absorbed by the intestine. This amount is already considerable. After 3 to 5 years of blood transfusion in these cases, it has greatly exceeded the iron storage of normal adults. The value is 1.5g.

(3) Bassett et al. proposed in 1986: hepatic iron index = mol iron / g hepatic dry weight ÷ age, identification of homozygotes and heterozygotes, alcoholic liver disease and small iron concentration increased with age The identification has a certain significance. The normal liver iron index is about 1.0, the hemochromatosis homozygote is greater than 2.0, the heterozygote and alcoholic liver disease are less than 1.8, and the hemochromatosis heterozygotes are lower than the alcoholic liver disease (Summers et al., 1990).

Local hemoheminosis mainly occurs in the lungs, kidneys, severe hemosiderin can lead to iron deficiency, and delayed porphyria (PCT) is a condition characterized by defects in porphyrin biosynthesis. Sometimes it can be accompanied by excessive iron deposition in the parenchymal organs. The increase in iron load in PCT is usually not enough to cause tissue damage. Some patients are accompanied by hepatitis C infection. Alcoholic liver disease may increase in tissue iron storage and reach HC. The degree of C282Y and other gene detection can be identified.

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