coenzyme in the metabolism of pyruvate and in the transketolase reaction Deficiency produces a disease known as beriberi, which has been related to diets consisting of polished rice in Asian societies and to alcoholism in the Occident Classically, the disease has been divided into two major types In dry beriberi, the patients have peripheral neuropathy with varied disorders of sensation, sometimes amounting to anesthesia, muscle weakness and atrophy, reduced deep tendon reflexes, fatigue, and difficulty concentrating In contrast, in wet beriberi, where the presenting features are a high-output cardiac failure with peripheral edema, the patients have diminished peripheral vascular resistance as a result of muscular arteriolar vasodilation, a wide pulse pressure, and a warm skin The mechanism leading to a reduction of peripheral vascular resistance is believed to be directly related to the lack of thiamine, since after treatment this parameter returns rapidly to normal.309 Despite the high cardiac output, oliguria is present owing to reduction of renal blood flow and glomerular filtration rate Increased jugular venous pressure results from peripheral venoconstriction and an increase in the circulating blood volume.310 Cutaneous vasoconstriction becomes evident with the progression of cardiac failure, which results in cold hands and peripheral cyanosis It is not clear whether the cardiac failure results from primary myocardial involvement or whether it is secondary to the vascular changes In some patients the additional toxic effects of alcohol make this differentiation very difficult Histologic studies of the heart have shown hydropic degeneration, interstitial and perivascular edema, and fibrosis and necrosis of myocardial tissue.311 An acute variant of the disease with vascular collapse, metabolic acidosis, and variable cardiac output is known as shoshin beriberi Patients present in severe biventricular failure They have renal dysfunction leading to metabolic acidosis There is a high arterial saturation of oxygen secondary to tachypnea, which contrasts with the peripheral cyanosis caused by cutaneous vasoconstriction.312 Cardiac catheterization reveals increased right and left atrial pressures and a low peripheral vascular resistance.313 Early diagnosis is necessary because patients die rapidly if left untreated The presentation varies with age Affected infants are very rarely seen in Western countries It appears in nursing babies of thiamine-deficient mothers around 1 to 4 months of age Sometimes the clinical onset is sudden Acute CHF may then appear in apparently healthy babies following a minor illness In others, signs and symptoms mimicking meningitis are seen Administration of thiamine produces a rapid recovery Beyond infancy, the dry form is seen in children fed polished rice Signs and symptoms are of peripheral neuropathy Cardiovascular involvement and edema are rare When the disease presents in adolescence, alcohol consumption must be considered in addition to poor dietary intake Patients manifest malaise, fatigue, palpitations, dyspnea, and peripheral edema They have an increased jugular venous pressure, a high pulse pressure, a gallop rhythm with nonspecific apical systolic murmurs, and a loud pulmonary component to the second heart sound There is cardiomegaly on the chest radiograph in half, and the ECG shows nonspecific T-wave changes Hemodynamic studies reveal a high cardiac index, stroke index, and circulating blood volume and low peripheral vascular resistance Clinical suspicion and a dietary history of poor thiamine intake and/or excessive consumption of alcohol are necessary for diagnosis Patients with beriberi exhibit low transketolase activity in erythrocytes, which increases after the administration of thiamine pyrophosphate Patients have low levels of thiamine in their blood and urine An acute response to intravenous thiamine during cardiac catheterization, with an increase in peripheral vascular resistance and a reduction in cardiac output, has also been used as a diagnostic test.314 Beriberi is a treatable cause of cardiac failure There is a rapid response to administration of thiamine Parenteral therapy is necessary in extreme cases Administration can later be continued orally Bed rest, oxygen, diuretics, and digitalis are useful therapeutic adjuncts Shoshin beriberi is a medical emergency that is fatal without aggressive medical management Correction of the acidosis with sodium bicarbonate is essential, together with the measures already described A balanced diet—with an adequate intake of meat, fresh vegetables and whole grains—will supply the daily requirements of thiamine and prevent beriberi Deposition Diseases The major disease caused by disordered deposition that arises in childhood is hemochromatosis The other depositions, such as amyloidosis, do not usually manifest prior to adulthood Hemochromatosis Hemochromatosis results from the deposition of iron It may be primary and hereditary or it may be secondary Primary or hereditary hemochromatosis results from the excessive absorption of iron from the diet The normal rate of intestinal iron absorption is 1 to 2 mg/day, but this can increase when necessary In patients with hemochromatosis, intestinal iron absorption can be as high as 8 to 10 mg/day Also, most iron in the plasma is stored in macrophages, and in patients with hemochromatosis, macrophages more readily release their stores of iron Intestinal absorption and macrophage release are under the control of hepcidin, an antimicrobial peptide synthesized by the liver Hepcidin acts to downregulate absorption and release through its degradation of ferroportin, a membrane protein critical for the uptake and release of iron Synthesis of hepcidin is regulated by multiple proteins in response to the need for and availability of iron Thus defects involving the hepcidin gene, the genes encoding its regulator proteins, or the ferroportin gene can all promote the excessive uptake and release of iron, leading to deposition in the organs These disorders are inherited in an autosomal recessive fashion The specific gene affected determines the clinical phenotype.315 Secondary hemochromatosis is generally the result of excessive administration of iron through multiple blood transfusions in chronic transfusion-dependent nonhemorrhagic anemias The most frequent of these is βthalassemia Each 250 mL of blood delivers approximately 200 mg of iron.316 Cardiac dysfunction generally occurs after 100 units of blood have been transfused.317 Although the primary and secondary diseases are quite different, the damaging effects of iron are similar The excess iron in the tissues weakens the lysosomal membranes and produces damage to the cells Damage to organs due to primary hemochromatosis generally appears between 40 and 60 years of age, although those with the more rare juvenile form can exhibit symptoms much earlier Cardiac involvement occurs in one in three