179 HEMOCHROMATOSIS, PORPHYRIAS, AND WILSON’S DISEASE
Harrison’s Manual of Medicine
HEMOCHROMATOSIS, PORPHYRIAS, AND WILSON’S DISEASE
Hemochromatosis is a disorder of iron storage that results in increased intestinal iron absorption with Fe deposition and damage to many tissues, including the liver, heart, pancreas, joints, and pituitary. Two major causes of hemochromatosis exist: hereditary (due to inheritance of mutant HFE genes) and secondary iron overload (usually the result of disordered erythropoiesis or excessive Fe ingestion). Alcoholic liver disease and chronic excessive iron ingestion may also be associated with a moderate increase in hepatic Fe and elevated body Fe stores.
Clinical Features Early symptoms include weakness, lassitude, weight loss, a bronze pigmentation or darkening of skin, abdominal pain, and loss of libido. Hepatomegaly occurs in 95% of pts, sometimes in the presence of normal LFTs. Other signs include spider angiomas, splenomegaly, arthropathy, ascites, cardiac arrythmias, CHF, loss of body hair, palmar erythema, gynecomastia, and testicular atrophy. Diabetes mellitus occurs in about 65%, usually in pts with family history of diabetes. Adrenal insufficiency, hypothyroidism, and hypoparathyroidism rarely occur.
Diagnosis Serum Fe, percent transferrin saturation, and serum ferritin levels are increased (Table 179-1). If either the percent transferrin saturation or the serum ferritin level is abnormal, genetic testing for hemochromatosis should be performed. All first-degree relatives of pts with hemochromatosis should be tested for the C282Y and H63D mutations. Liver biopsy may be required in affected individuals to evaluate possible cirrhosis or to quantify tissue iron. An algorithm for evaluating pts with possible hemochromatosis is shown in Fig. 179-1. Death in untreated pts results from cardiac failure (30%), cirrhosis (25%), and hepatocellular carcinoma (30%); the latter may develop despite adequate Fe removal.
Table 179-1 Representative Iron Values in Normal Subjects, Patients with Hemochromatosis, and Patients with Alcoholic Liver Disease
FIGURE 179-1. Algorithm for screening for HFE-associated hemochromatosis. LFT, liver function tests; TS, transferrin saturation. (With permission from The Canadian Journal of Gastroenterology.)
Involves removal of excess body Fe, usually by intermittent phlebotomy. Since 1 unit of blood contains ~250 mg Fe, and since ³25 g of Fe must be removed, phlebotomy is performed weekly for 1–2 years. Less frequent phlebotomy is then used to maintain serum Fe at <27 µmol/L (<150 µg/dL). Chelating agents such as deferoxamine (infused SC using a portable pump) remove 10–20 mg iron per day, a fraction of that mobilized by weekly phlebotomy. Chelation therapy is indicated, however, when phlebotomy is inappropriate.
The porphyrias are inherited or acquired disturbances in heme biosynthesis. Each disorder causes a unique pattern of overproduction, accumulation, and excretion of intermediates of heme synthesis (Table 179-2). Manifestations include intermittent nervous system dysfunction and/or sensitivity of skin to sunlight.
Table 179-2 The Major Metabolites Accumulated in the Human Porphyrias
ACUTE INTERMITTENT PORPHYRIA This is an autosomal dominant disorder with variable expressivity. Manifestations include colicky abdominal pain, vomiting, constipation, port-wine colored urine, and neurologic and psychiatric disturbances. Acute attacks rarely occur before puberty and may last from days to months. Photosensitivity does not occur. Clinical and biochemical manifestations may be precipitated by barbiturates, anticonvulsants, estrogens, oral contraceptives, alcohol, or low-calorie diets. Diagnosis is established by demonstrating elevation of urinary porphobilinogen (PBG) and g-aminolevulinic acid (ALA) during an acute attack. Fresh urine may darken on standing because PBGs polymerize spontaneously to uroporphyrin and porphobilin.
As soon as possible after the onset of an attack, 3–4 mg of heme, in the form of heme arginate, heme albumin, or hematin, should be infused daily for 4 days. Administration of IV glucose at rates up to 20 g/h or parenteral nutrition, if oral feeding is not possible for long periods, can be effective in acute attacks. Narcotic analgesics may be required during acute attacks for abdominal pain, and phenothiazines are useful for nausea, vomiting, anxiety, and restlessness. Treatment between attacks involves adequate nutritional intake, avoidance of drugs known to exacerbate the disease, and prompt treatment of other intercurrent diseases or infections.
PORPHYRIA CUTANEA TARDA This is the most common porphyria and is characterized by chronic skin lesions and, usually, hepatic disease. It is due to deficiency (inherited or acquired) of uroporphyrinogen decarboxylase. Photosensitivity causes facial pigmentation, increased fragility of skin, erythema, and vesicular and ulcerative lesions, typically involving face, forehead, and forearms. Neurologic manifestations are not observed. Contributing factors include excess alcohol, iron, and estrogens. Pts with liver disease are at risk for hepatocellular carcinoma. Urine uroporphyrin and coproporphyrin are increased.
Avoidance of precipitating factors, including abstinence from alcohol, estrogens, iron supplements, and other exacerbating drugs, is the first line of therapy. A complete response can almost always be achieved by repeated phlebotomy (every 1–2 weeks) until hepatic iron is reduced. Chloroquine or hydroxychloroquine may be used in low doses (e.g., 125 mg chloroquine phosphate twice weekly) to promote porphyrin excretion in pts unable to undergo or unresponsive to phlebotomy.
ERYTHROPOIETIC PORPHYRIAS In the erythropoietic porphyrias, porphyrins from bone marrow erythrocytes and plasma are deposited in the skin and lead to cutaneous photosensitivity. The disorders include X-linked sideroblastic anemia, congenital erythropoietic porphyria, and erythropoietic protoporphyria. Diagnosis and treatment vary depending on the type of porphyria but often require transfusions to suppress erythropoiesis and avoidance of exposure to sunlight.
Wilson’s disease is an inherited disorder of copper metabolism, resulting in the toxic accumulation of copper in the liver, brain, and other organs. Individuals with Wilson’s disease have mutations in the ATP7B gene.
Clinical Features In about half of pts, one of four types of hepatic disease herald the clinical onset: acute hepatitis, parenchymal liver disease, cirrhosis, or fulminant hepatitis. In most other pts, neurologic or psychiatric disturbances are the first clinical sign and are always accompanied by Kayser-Fleischer rings (corneal deposits of copper). In about 5% of pts, the first manifestation may be primary or secondary amenorrhea or repeated spontaneous abortions.
Diagnosis The diagnosis is confirmed by a serum ceruloplasmin level <200 µg/L (< 20 mg/dL) and either (1) Kayser-Fleischer rings or (2) an elevated copper level on liver biopsy.
Penicillamine is administered in an initial dose of 1 g PO qd on an empty stomach, along with 25 mg of pyridoxine. Penicillamine should be discontinued if rash, fever, leukopenia, thrombocytopenia, lymphadenopathy, proteinuria, or neurologic features worsen. It can be replaced with trientine, 250 mg PO qid, given on an empty stomach.
For a more detailed discussion, see Powell LW, Isselbacher KI: Hemochromatosis, Chap. 345, p. 2257; Desnick RJ: The Porphyrias, Chap. 346, p. 2261; Scheinberg IH: Wilson’s Disease, Chap. 348, p. 2274, in HPIM-15.