Nutritional and Metabolic Diseases

Beriberi

Beriberi is a nutritional deficiency state that is caused directly by a lack of thiamine (vitamin B ₁ ) in one's diet or by a lack of proper absorption of the vitamin. A rare form of acquired thiamine deficiency occurs after the ingestion of thiaminase, an enzyme that cleaves thiamine into a nonfunctional state. These cases are exceedingly rare and are considered to occur after an accidental poisonous ingestion of a source high in thiaminase. Thiamine deficiency is a rare occurrence in most of the world but is still seen in people whose food supply is based primarily on polished rice. The other major cause of the disease is alcoholism. Alcoholics who obtain most of their caloric intake from alcohol may be deficient in a multitude of B vitamins including thiamine. Thiamine deficiency may be seen in neonates and infants who are breast feeding from mothers with borderline thiamine deficiency. The principal food sources of thiamine are fresh meats, liver, whole wheat bread, and vegetables. Nonpolished brown rice is also a good source of thiamine. Thiamine is absorbed in the gastrointestinal tract in the proximal jejunum.

Thiamine deficiency has been reported in cases of short gut syndrome and after bariatric surgery in which large parts of the jejunum are bypassed and absorption of thiamine is dramatically decreased. Most of these cases were complicated by the fact that patients were not following their prescribed diets. Beriberi has also been reported in patients with human immunodeficiency virus infection and in some people taking long-term furosemide therapy without adequate thiamine intake. Furosemide has been shown to increase the rate of excretion of thiamine from the kidneys.

Thiamine is a water-soluble vitamin that is critical in the formation of the energy storage molecule, adenosine triphosphate (ATP). Thiamine is crucial for the proper functioning of both glycolysis and the Krebs cycle. The U.S. Nutrition Board of the Institute of Medicine, National Academy of Sciences, has designated 1.2 mg/day of thiamine as the normal recommended daily intake for men and 1.1 mg/day for women.

Clinical Findings: The disease is most frequently seen in Asia, where polished rice is one of the main food sources. Alcoholics are at very high risk for development of this vitamin deficiency. There is no race or gender predilection, and it can occur in all people. The clinical findings in beriberi are highly variable and are dependent on the level of deficiency and the patient's underlying comorbidities. The organ systems most commonly involved are the central nervous system (CNS) and the muscular system. Two major forms of beriberi occur, although there is much overlap. Dry beriberi is a form of the disease in which the CNS symptoms predominate. Wet beriberi is the form in which the predominant symptoms are salt retention and congestive heart failure. Infantile beriberi is rare but is manifested by a combination of dry and wet beriberi with severe CNS depression, heart failure, and sudden death.

The first signs and symptoms of dry beriberi are typically those of a peripheral neuropathy and of muscle disease involving both skeletal and smooth muscle. Dry beriberi typically manifests with increasing fatigability, muscle weakness, paresthesias, a decrease in deep tendon reflexes, and loss of sensation. As the disease progresses, patients may develop a foot or wrist drop (flaccid paralysis). The lower extremity is typically affected before the upper. Loss of muscle mass may be prominent. Elevated levels of creatinine phosphokinase are seen, as well as a creatinuria. Weakness is profound.

Wet beriberi predominantly affects the muscle tissue, particularly the cardiac system. The end stage is high-output cardiac failure; without treatment, death follows. Beriberi rarely causes death if the diagnosis is made and proper treatment is instituted before end-stage heart failure sets in. Patients with wet beriberi experience a decrease in diastolic blood pressure and minimal change in systolic pressure, resulting in an overall increase in the pulse pressure. Tachycardia is prominent. As heart failure develops, pulmonary edema and fluid retention occur, causing dependent edema and difficulty breathing. Cyanosis may occur from poor oxygenation. Laboratory testing shows an increased QT interval on electrocardiography and increased serum levels of lactic acid, pyruvate, and α-ketoglutarate. Chest radiography shows an enlarged heart with dilation of the right side and pulmonary congestion, edema, or both.

The skin findings of beriberi are not specific, but when seen in conjunction with the rest of the clinical picture, they can definitely help make the diagnosis. The cutaneous findings of wet beriberi consist of cyanosis of the skin with variable amounts of peripheral edema. The skin has a waxy appearance and feel. Cutaneous pallor is prominent and, along with the cyanosis, gives the patient an ill appearance. Pallor is a common skin finding in dry beriberi as well. Patients may also present with accidental traumatic injuries to their extremities related to lack of sensation from the peripheral neuropathy. Hair loss has been reported, but most believe that this is secondary to a combination of niacin and thiamine deficiency.

The excretion of thiamine via the kidneys is markedly decreased in beriberi. Normally, 70 to 150 µg of thiamine is excreted per gram of creatinine. In beriberi, that level can drop to zero.

Histology: Biopsy specimens of the skin in patients with beriberi are of no clinical usefulness. A skin biopsy from an area of cyanosis or pallor shows normal skin. A biopsy from one of the waxy areas may show variable mild degrees of acanthosis and parakeratosis. A muscle biopsy shows vacuolization and hyalinization of the muscle fibers. An inflammatory process may be present that can cause varying degrees of necrosis of the muscle. The muscle fibers may show diffuse or focal fiber necrosis. These changes are most prominent in the cardiac muscle. In patients who develop Wernicke's syndrome, postmortem examinations of the brain have revealed small hemorrhages within the hypothalamus and upper brainstem. Peripheral nerve tissue shows noninflammatory degeneration of the neurons with atrophy and chromatolysis. This can occur in the neurons of the peripheral nervous system and the CNS.

Pathogenesis: All forms of beriberi are caused by a nutritional deficiency of thiamine. Thiamine is a critical vitamin that is needed for carbohydrate metabolism. Thiamine is the precursor for thiamine pyrophosphate (TPP). It is converted to TPP by the addition of one ATP molecule. TPP is needed as a cofactor for the proper function of many metabolic pathways. TPP helps transfer an aldehyde group from a donor to a beneficiary chemical structure. Three major energy-producing pathways are modulated by TPP: glycolysis, the Krebs cycle, and the pentose shunt (hexose monophosphate shunt). The hexose monophosphate shunt is important in producing other cofactors that play important biochemical roles for donation of hydrogen. The overall chemical state that occurs in patients with thiamine deficiency is a lack of ability to produce sufficient quantities of cellular ATP. This lack of the main source of energy for the cell results in the clinical findings. The nervous tissue and muscle tissue are particularly prone to damage from failure to produce sufficient ATP. It has been estimated that 3 to 6 weeks of a thiamine-free diet in an average human is sufficient to cause development of the initial signs and symptoms of beriberi.

Treatment: Therapy consists of supplementation of the patient's diet with 50 mg/day intramuscularly of thiamine until the symptoms resolve. Treatment should also include other B-complex vitamins, because many patients who are deficient in one B vitamin also have low levels of the others. A nutritionist should be consulted to educate the patient on the need for a proper diet and how to achieve this. Alcoholics are prone to recurrence of beriberi and should be encouraged to participate in alcohol abstinence programs and to take a daily multivitamin supplement. The symptoms rapidly reverse on replacement of thiamine.

Hemochromatosis

Hemochromatosis is a fairly common autosomal recessive genetic disorder of iron metabolism that leads to excessive iron absorption and eventually iron overload. Iron progressively accumulates in various tissues throughout the body, with the liver most severely affected. Most cases are caused by a genetic mutation in the hemochromatosis gene, HFE . This mutation is carried by approximately 10% of the population. The disease signs and symptoms typically do not appear until after child-bearing age, usually in the sixth or seventh decade of life.

Clinical Findings: Caucasian males are the most frequently affected, and there is variability of carrier rates among populations. For example, in Ireland the rate of homozygosity for the C282Y mutation in HFE is 1 in 85 individuals. The overall incidence worldwide is probably about 1 in 350.

The clinical manifestations of hemochromatosis patients who are homozygous for the mutated HFE gene can be quite variable. Classic hemochromatosis includes three main components: liver cirrhosis, diabetes, and generalized skin pigmentation. These symptoms are caused, respectively, by a persistent chronic accumulation of iron in the liver and in the pancreas and by iron deposition in the skin with increased melanin production. Cirrhosis is the main cause of morbidity and mortality, and it dramatically increases one's risk for hepatocellular carcinoma.

Cutaneous findings include a generalized bronze discoloration of the skin. This diffuse pigmentation is one of the first signs of the disease. This finding, along with diabetes, has led to the name “bronze diabetes” to describe the condition. Nails can be brittle and show varying degrees of koilonychia. There is widespread generalized hair thinning and loss, affecting all terminal hair locations. Arthritis is a common finding in these patients and can also be seen in asymptomatic heterozygous carriers of the disease.

Histology: Histology of the skin is not useful for diagnosis. Liver biopsies show varying degrees of damage on a spectrum from fibrosis to cirrhosis. The Prussian blue stain is used to accentuate the iron within the hepatocytes and the cells of the biliary tract. There is less iron accumulation in the Kupffer cells, which is the direct opposite of the findings in states of iron overload.

Pathogenesis: The HFE gene is located on the short arm of chromosome 6 and is mutated in this autosomal recessive genetic disorder of iron metabolism. The most frequently encountered genetic mutation is the C282Y mutation. Normal iron regulation is dependent on absorption of iron from dietary sources and normal losses. Regulatory mechanisms allow for equalization of iron absorption to balance the iron losses in normal physiological states. The defect in HFE leads to abnormal regulation of cellular uptake of iron as well as a loss of regulation of ferritin levels. The result of the excessive iron deposition is an increase in free radical oxygen species and their destructive interactions with various tissues. In the liver, this leads to fibrosis and eventually cirrhosis.

Treatment: Therapy requires removal of the excessive iron. This is best accomplished by routine scheduled phlebotomy. Phlebotomy decreases the amount of iron stores and is used to attempt to prevent the progression to cirrhosis. Prevention of cirrhosis is the single best predictor of morbidity and mortality in these patients. The goal in most patients is to keep the hemoglobin in the range of 12 g/dL. Other methods to remove excessive iron include erythrocytapheresis and iron chelation therapy. Erythrocytapheresis is a method by which predominantly red blood cells are removed from the blood while the serum, white blood cells, and platelets are returned to the patient's bloodstream. Iron chelation therapy with intravenous deferoxamine has been helpful for patients who cannot tolerate blood removal procedures. Methods to try to decrease the absorption of iron from the gastrointestinal tract can also be attempted. These treatments have shown the best results if implemented before evidence of cirrhosis is present. The importance of genetic counseling cannot be overemphasized.