PBL Sessions: Musculoskeletal Organ System

Page 10

Final Discussion of Case:

Case Summary:

Key Issues: The patient is a 54-year-old man who has had worsening joint aches and pains for the past 4 years.

Pathologic / Radiologic Learning Issues:

• Causes for arthritis/arthragia

• Laboratory testing for arthritides

• Causes for gout

• Causes for hemochromatosis

• Pathophysiology of hereditary hemochromatosis

• Pathophysiology of gout

Clinical Learning Issues

• Workup for arthritis/arthragia

• Interpretation of laboratory findings with application to the clinical seting

• Use of pharmacologic agents in arthritis

• Significance of genetic testing

Discussion

Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is one of the most common genetic diseases. It is most common in populations of northern European descent: about 1 in 10 such persons are heterozygous carriers and 0.3 to 0.5% are homozygotes. However, expression of the disease is modified by dietary iron intake, blood loss associated with menstruation and pregnancy, and blood donation. The clinical expression of the disease is 5 to 10 times more frequent in men than in women. Most male patients develop the first symptoms between ages 40 and 60, while female patients may have the onset of symptoms after age 60. HH is rare before age 20, although with family screening and physical examinations, asymptomatic patients can be identified. Penetrance of the mutation is variable.

The HH gene, cloned in 1996, is called HFE. A homozygous G to A mutation resulting in a cysteine to tyrosine substitution at position 282 (C282Y) is the most common mutation. It has been found in 85 to 100% of HH patients of northern European descent, but is present in only 60% of cases from Mediterranean populations. The second most common HFE mutation results in an amino acid substitution of histidine to aspartic acid at position 63 (H63D). Some compound heterozygotes (e.g., one copy each of C282Y and H63D) have increased body iron stores. Thus, HFE associated hemochromatosis is inherited as an autosomal recessive trait; heterozygotes have no, or minimal, increase in iron stores. HH manifests itself either from homozygotes for C282Y or compound heterozygotes for C282Y / H63D.

Total adult body iron is normally 3 to 6 gm and varies little because intestinal mucosal absorption of iron is equal to iron loss from sloughed epithelial cells (or menstrual blood loss in women). This amount is approximately 1 mg/d in men and 1.5 mg/d in menstruating women. In hemochromatosis, mucosal absorption is inappropriate to body needs and amounts to 4 mg/d or more. The progressive accumulation of iron causes an early elevation in plasma iron, an increased saturation of transferrin, and progressive elevation of plasma ferritin level.

The HFE gene encodes a 343 amino acid protein that is structurally related to MHC class I proteins. The basic defect in hemochromatosis is a lack of cell surface expression of HFE (due to the C282Y mutation). The normal (wild type) HFE protein forms a complex with Beta2-microglobulin and transferrin, and the C282Y mutation eliminates this interaction. As a result, the mutant HFE protein remains trapped intracellularly, reducing transferrin receptor-mediated iron uptake by the intestinal crypt-cell. This is postulated to upregulate the divalent metal transporter (DMT-1) on the brush border of the villous cells, leading to inappropriately increased intestinal iron absorption. In advanced disease, the body may contain 20 g or more of iron that is deposited mainly in parenchymal cells of the liver, pancreas, and heart. Iron may be increased 50- to 100-fold in the liver and pancreas and 5- to 25-fold in the heart. Iron deposition in the pituitary causes hypogonadotropic hypogonadism in both men and women. Tissue injury may result from disruption of iron-laden lysosomes, from lipid peroxidation of subcellular organelles by excess iron, or from stimulation of collagen synthesis by activated stellate cells.

Initial symptoms include weakness, lassitude, weight loss, change in skin color, abdominal pain, loss of libido, and symptoms of diabetes mellitus. Hepatomegaly, increased pigmentation, spider angiomas, splenomegaly, arthropathy, ascites, cardiac arrhythmias, congestive heart failure, loss of body hair, testicular atrophy, and jaundice are prominent in advanced disease.

The liver is usually the first organ to be affected, and hepatomegaly is present in more than 95% of symptomatic patients. Over half of patients with symptomatic hemochromatosis have little laboratory evidence of functional impairment of the liver, in spite of hepatomegaly and fibrosis. Manifestations of portal hypertension and esophageal varices occur less commonly than in cirrhosis from other causes. Hepatocellular carcinoma develops in about 30% of patients with cirrhosis with HH, and it is the most common cause of death in treated patients.

Excessive skin pigmentation is present in over 90% of symptomatic patients at the time of diagnosis. The characteristic metallic or slate gray hue is sometimes referred to as bronzing and results from increased melanin and iron in the dermis. Pigmentation usually is diffuse and generalized, but it may be more pronounced on the face, neck, extensor aspects of the lower forearms, dorsa of the hands, lower legs, genital regions, and in scars.

Diabetes mellitus occurs in 2/3 of patients and is more likely to develop in those with a family history of diabetes, suggesting that direct damage to the pancreatic islets by iron deposition occurs in combination with a genetic predisposition. The management is similar to that of other forms of diabetes.

Arthropathy develops in 25 to 50% of patients. It usually occurs after age 50, but may occur as a first manifestation, or long after therapy. The joints of the hands, especially the second and third metacarpophalangeal joints, are usually the first joints involved. A progressive polyarthritis involving wrists, hips, ankles, and knees also may ensue. Acute brief attacks of synovitis may be associated with deposition of calcium pyrophosphate (chondrocalcinosis or pseudogout), mainly in the knees. Radiologic manifestations include cystic changes of the subchondral bones, loss of articular cartilage with narrowing of the joint space, diffuse demineralization, hypertrophic bone proliferation, and calcification of the synovium. The arthropathy tends to progress despite removal of iron by phlebotomy. Although the relation of these abnormalities to iron metabolism is not known, the fact that similar changes occur in other forms of iron overload suggests that iron is directly involved.

Cardiac involvement is the presenting manifestation in about 15% of patients. The most common manifestation is congestive heart failure. Symptoms of congestive failure may develop suddenly, with rapid progression to death if untreated. The heart is diffusely enlarged and may be misdiagnosed as idiopathic cardiomyopathy if other overt manifestations are absent. Cardiac arrhythmias commonly occur.

Hypogonadism occurs in both sexes and may antedate other clinical features. Manifestations include loss of libido, impotence, amenorrhea, testicular atrophy, gynecomastia, and sparse body hair. These changes are primarily the result of decreased production of gonadotropins due to impairment of hypothalamic pituitary function by iron deposition; however, primary testicular dysfunction may be seen in some cases. Adrenal insufficiency, hypothyroidism, and hypoparathyroidism may also occur.

The association of (1) hepatomegaly, (2) skin pigmentation, (3) diabetes mellitus, (4) heart disease, (5) arthritis, and (6) hypogonadism should suggest the diagnosis of HH. When the diagnosis of hemochromatosis is established, it is important to counsel and screen other family members. Asymptomatic as well as symptomatic family members with the disease usually have an increased saturation of transferrin and an increased serum ferritin concentration. These changes occur even before the iron stores are greatly increased. All first-degree relatives of patients with hemochromatosis should be tested for the C282Y and H63D mutations and advised appropriately. In affected individuals, it is important to confirm or exclude the presence of cirrhosis, and begin therapy as early as possible.

Therapy for hemochromatosis involves removal of the excess body iron by weekly or twice-weekly phlebotomy of a unit of blood (500 mL). Although there is an initial decrease in hematocrit to 35%, the level stabilizes after several weeks. The plasma ferritin concentration continues to fall along with the gradual decrease in body iron stores. Since one unit of blood contains 250 mg iron, and about 25 g of total body iron needs to be removed, weekly phlebotomy may be required for 1 or 2 years. When the ferritin level become normal, phlebotomy is done 3 or 4 times per year to keep iron stores within the normal range. Chelating agents such as deferoxamine, when given parenterally, remove 10 to 20 mg iron per day, less than weekly phlebotomy, and has toxicity. Phlebotomy is more convenient and safer for most patients. The chelating agents are indicated when anemia is severe enough to preclude phlebotomy.

The management of hepatic failure, cardiac failure, and diabetes mellitus is similar to conventional therapy for these conditions. Loss of libido and change in secondary sex characteristics are partially relieved by parenteral testosterone or gonadotropin therapy.

The cause of death in untreated HH patients is usually cardiac failure (30%), hepatocellular failure or portal hypertension (25%), or hepatocellular carcinoma (30%).

Life expectancy is improved by removal of the excessive stores of iron and maintenance of these stores at near-normal levels. The 5-year survival rate with therapy increases from 33 to 89%. With phlebotomy, hepatosplenomegaly decreases, liver function improves, skin pigmentation diminishes, and cardiac failure lessens. Diabetes mellitus is lessened in about 40% of HH patients. However, hypogonadism and arthropathy often persist.

As with all genetic illnesses, this disease raises the conflict between the privacy of your patient and the usefulness of testing for other family members, or between the patient and insurers. If you say that the patient should be tested, you are as much as revealing confidential information about your patient.

Furthermore, there are ancillary issues: who should be allowed to test a minor? What if the test is of no benefit, if there is no current treatment? Could it affect how the parents treat the child, or otherwise affect the child's life negatively? What if the test reveals some surprising information about paternity (or non-paternity)?

Genetics issues challenge traditional ideas of patient autonomy, and will become of growing importance by leaps and bounds over the next decade or two, thanks to the Human Genome Project and its medical aftermath.

Gout

Gout typically presents with a sudden attack, often at night, with severe pain and swelling in the affected joint. The overlying skin may be erythematous. Gouty attacks are usually monoarticular, or involve just a few joints. The feet and ankles are most often affect, and the first MP joint is the most common site of involvement. Without treatment the attack subsides in a week or so, and when patients first develop gout there may be intervals of many months or even years between attacks. Over time the attacks tend to become more frequent and severe. Eventually many joints may be involved. sometimes all at the same time. A stage of chronic or continuous joint disease may develop with progressive joint damage with disability and crippling arthritis. Gout affects mostly men and is very rare in women until after the menopause when it is quite often seen.

Gout is due to the accumulation of sodium urate crystals in joins and soft tissues. Most patients with gout have hyperuricemia, but some do not. Gout can be associated with:

• Family history

• Obesity

• High alcohol intake, particularly red wine

• High intake of food containing purines such as liver, kidneys, tripe, sweetbreads and tongue, excessive amounts of red meat, shellfish, fish roe and scallops, peas. lentils and beans

• Some of the drugs used to treat high blood pressure.

The non-steroidal anti-inflammatory drugs (NSAIDSs) can be effective for therapy. Treatment should start as soon as possible at the first sign of an attack. With effective treatment the attack may be controlled within 12-24 hours and treatment continued for only a few days. Rest and elevation of the affected joint along with increased fluid intake are helpful. Drugs used for the acute attack have no effect on reducing uric acid levels.

If hyperuricemia persists despite dietary modifications and attacks continue or become more frequent, drugs can be used which directly lower the blood uric acid. However, it must be understood that these drugs have no effect on the actual attacks of acute gout and they must be taken on a continuous basis. The dose must be adjusted based on the blood uric acid levels. Once the uric acid is within the normal range, the patient usually does not have acute attacks. Patients beginning long-term drug therapy for gout may have more frequent and severe gouty attacks within the first few months.

Chronic gout leads to deposition of urates in and around affected joints and even in soft tissues elsewhere such as the ears. These deposits are known as tophi. The appearance of tophi means that long-term drug therapy is needed. Hyperuricemia and recurrent gout are often associated with high blood pressure leading to renal damage and chronic renal failure.