bubble_chart Overview

Hemochromatosis is a rare congenital metabolic disorder caused by excessive iron deposition in organ tissues, leading to varying degrees of parenchymal cell damage, fibrous tissue hyperplasia, and organ dysfunction. Clinical manifestations include liver cirrhosis, diabetes, skin pigmentation, endocrine disorders, as well as cardiac and joint lesions.

bubble_chart Pathogenesis

The pathogenesis of hemochromatosis mainly involves gene abnormalities on the sixth pair of chromosomes, leading to increased iron absorption in the small intestine mucosa from food, resulting in elevated iron levels in the body—exceeding the normal range by 5 to 10 times. Tracer isotope studies indicate that patients with hemochromatosis can absorb 20% to 45% of orally ingested iron (compared to 1.5% to 4.4% in healthy individuals). Excessive iron deposition in the body causes liver damage and cirrhosis through three proposed mechanisms: ① In the acidic environment of lysosomes, hemosiderin releases iron, destabilizing the lysosomal membrane and allowing hydrolytic enzymes to enter the cytoplasm, causing damage; ② Excess free iron induces lipid peroxidation in organelle lipids, further damaging mitochondria and cell membranes, leading to cell death; ③ Excessive iron in the liver directly stimulates collagen fiber synthesis, resulting in liver fibrosis and cirrhosis.

bubble_chart Pathological Changes

The most prominent pathological changes are the deposition of varying amounts of iron-containing pigments (hemosiderin, ferritin) and non-iron-containing pigments (lipofuscin and melanin) in the parenchymal cells of various organs, accompanied by fibrosis.

I. Liver

The iron content in the liver is often 50–100 times the upper limit of normal liver iron levels. The most significant abnormality is the presence of hemosiderin granules in hepatocytes, primarily distributed around the tubules. In advanced stages, iron deposits are also found in the epithelial cells of bile ducts, Kupffer cells, and macrophages. Non-specific changes include fatty degeneration and vacuolar degeneration. Almost all symptomatic patients exhibit hepatic fibrosis or cirrhosis, with fibrous septa of varying widths. The fibrous bundles originate around the portal veins and then extend to encircle one or several lobules, resembling the morphological changes seen in chronic partial bile duct obstruction. Iron deposits within the nodules are typically found in hepatocytes rather than fibrous tissue, suggesting that nodule formation results from the encapsulation by fibrous tissue rather than the proliferation of surviving hepatocytes.

II. Pancreas

Both endocrine and exocrine cells of the pancreas exhibit excessive iron deposition. In symptomatic cases, the pancreatic acinar structure is disrupted, with marked intralobular and interlobular fibrosis and a reduction in islet cells. Iron deposition in acinar cells and fibrous tissue is significantly more pronounced than in the Langerhans cells of the islets, indicating that endocrine cells are more sensitive to the toxic effects of iron.

III. Other Endocrine Glands

Hemosiderin deposits are found in the thyroid follicles, the zona glomerulosa of the adrenal medulla, the anterior pituitary cells (excluding acidophils), and the parathyroid glands. The seminiferous epithelium of the testes atrophies, but iron deposition is relatively minimal.

IV. Skin

The clinical observation of skin pigmentation is primarily due to melanin deposition in the basal layer of the epidermis. However, in atrophied dermis and epidermis, hemosiderin deposition in sweat glands, vascular endothelium, and dermal connective tissue can manifest as gray pigmentation.

V. Heart

The heart is markedly hypertrophied, with severe myocardial involvement and a reduction in muscle fibers. Hemosiderin deposits are present in the ventricular myocardium, with heavier deposition in the subendocardial membrane and contractile myocytes compared to the conduction tissue. Ferritin can be observed around the nuclei of myocardial cells, which undergo degeneration and necrosis, replaced by fibrous tissue.

VI. Joints

Synovial membrane cells contain abundant hemosiderin deposits, and the associated fibrous tissue also shows significant hemosiderin deposition. Ultrastructural studies reveal iron deposition in synthetic cells, fibroblasts, and chondrocytes, while macrophages are almost devoid of iron. Chondrocytes and surrounding cartilage tissue exhibit secondary degenerative changes, calcification, and the formation of subchondral cysts.

The spleen, bone marrow, brain, and nervous tissues are less severely affected.

bubble_chart Clinical Manifestations

Patients with hemochromatosis typically develop clinical symptoms when the body's iron stores reach 25–50g. The average age of symptom onset is 50 years, but early clinical manifestations caused by hemochromatosis are often overlooked, leading to a delay in diagnosis by 4–5 years. The condition is more common in males, with a male-to-female ratio of 8:1.

The primary symptoms of hemochromatosis include skin pigmentation, diabetes, cirrhosis, and hypogonadism. Due to advancements in modern diagnostic methods, some homozygous individuals without typical symptoms or even those who are asymptomatic can now be identified. A recent analysis of 163 patients revealed that 83% experienced fatigue and drowsiness, 58% had abdominal pain, 43% reported arthralgia, 38% exhibited decreased libido and impotence, and 15% showed symptoms of heart failure. Additionally, 69% had cirrhosis, 83% had hepatomegaly, 13% had splenomegaly, 20% experienced body hair loss, 8% of males had gynecomastia, 75% displayed skin pigmentation, and 55% had clinical diabetes.

I. Liver

Hepatomegaly precedes cirrhosis, and the degree of enlargement correlates with the extent of iron deposition. Among non-cirrhotic hemochromatosis patients, 69% have hepatomegaly, while 90% of cirrhotic patients exhibit hepatomegaly, suggesting that iron deposition itself plays a major role in liver pathology. After cirrhosis develops, liver dysfunction and portal hypertension often occur. Liver function tests may show decreased serum albumin, prolonged prothrombin time, and grade I elevation of transaminases. Other nonspecific manifestations of cirrhosis include decreased libido, impotence, amenorrhea, and gynecomastia.

The threshold for hepatic iron deposition leading to cirrhosis and fibrosis is 22mg/g dry weight. Cirrhosis increases the risk of liver cancer, with the incidence of hepatocellular carcinoma in hemochromatosis cirrhosis being 200 times higher than in the general population. Most cases are primary hepatocellular carcinomas, though some may originate from intrahepatic bile ducts. The incidence of extrahepatic cancer is relatively low.

Right upper abdominal pain is usually chronic but can sometimes be acute. Acute abdominal pain can be severe and may even lead to painful shock, though the exact cause remains unclear.

II. Diabetes

Among cirrhotic hemochromatosis patients, 71% have overt diabetes, with 60% being insulin-dependent and 31% non-insulin-dependent. In non-cirrhotic patients, 20% have clinical diabetes, of which 60% are non-insulin-dependent. Among the remaining hemochromatosis patients without overt diabetes, 31% exhibit abnormal glucose tolerance. For long-term survivors of hemochromatosis with diabetes who receive treatment, complications such as retinopathy, neuropathy, nephropathy, and peripheral vascular disease are similar to those seen in other forms of diabetes.

III. Skin Pigmentation

Almost all patients develop skin pigmentation, particularly in sun-exposed areas. However, due to its insidious progression, patients and their relatives often fail to notice it.

IV. Heart

One-third of patients experience arrhythmias, and 15% may develop heart failure. Electrocardiograms may show low voltage, T-wave changes, premature beats, atrial or ventricular fibrillation, and bundle branch block. Echocardiography may reveal generalized cardiac enlargement.

V. Joint Disorders

The incidence ranges from 43% to 57%, with only 55% of these patients reporting joint pain. Physical examination may reveal joint abnormalities, and even in asymptomatic cases with normal physical findings, X-rays may detect lesions such as cystic changes and marginal sclerosis. These changes are most common in the second and third metacarpophalangeal joints, though the knees and hips may also be affected. The incidence of joint disorders is unrelated to the presence of cirrhosis and may be the first or only manifestation of the disease.

VI. Endocrine Gland Abnormalities

Male patients may experience decreased libido and impotence, accompanied by changes in secondary sexual characteristics, which are often associated with liver involvement but usually appear before cirrhosis. Female amenorrhea is unrelated to the presence of cirrhosis. The incidence of gynecomastia in males is lower than in patients with cirrhosis caused by other factors and is also unrelated to the presence of cirrhosis. Most patients with hypogonadism exhibit decreased gonadotropin secretion, low luteinizing hormone levels, low follicle-stimulating hormone levels, and a diminished response to gonadotropin-releasing hormone.

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

bubble_chart Diagnosis

The diagnosis is not difficult for patients with obvious clinical symptoms. If the patient exhibits ① elevated serum iron, ② increased serum iron saturation, and ③ elevated serum ferritin, a liver biopsy should be performed for confirmation. Relevant values are listed in the table below.

Table: Iron Content in Various Forms in Hemochromatosis

The following diseases should be excluded: various types of cirrhosis, diabetes, Addison's disease, hepatolenticular degeneration, and spinal muscular atrophy.

bubble_chart Treatment Measures

Early diagnosis and early treatment are essential. For hemochromatosis patients who already have cirrhosis, the prognosis is poor, with a shortened lifespan and a high risk of developing liver cancer. However, for patients in the pre-cirrhotic stage, if the excess stored iron can be promptly removed, their lifespan will not be affected, and they will not develop liver cancer. Homozygotes identified by HLA typing, even without obvious iron overload, should undergo regular annual tests for transaminase, serum iron, transferrin saturation, and ferritin to detect early or existing iron overload and initiate early treatment.

The most fundamental treatment is phlebotomy to remove excess iron from the body. Each 500 ml of blood contains approximately 250 mg of iron. Phlebotomy of 500 ml is performed once a week or every two weeks until the excess iron is depleted, which generally takes 2–3 years. Afterward, maintenance phlebotomy is performed every 2–4 weeks as needed. Following phlebotomy, patients experience relief from systemic symptoms, weight gain, and reduced skin pigmentation and hepatosplenomegaly. For patients with heart failure, iron chelators such as deferoxamine (0.5 g intramuscularly twice daily) can be administered until cardiac function improves, after which phlebotomy can be resumed.

For complications such as cirrhosis with ascites, portal hypertension, diabetes, heart failure, and sexual dysfunction, symptomatic treatment should be provided.