Acute hemolytic anemia after ingestion of fava beans

Correspondence ACUTEHEMOLVTICANEMIAAFTERINGESTIONOF FAVABEANS To theEditor:-The case for discussion is a 46-year-old Middle Eastern male who presented to the emergency department (ED) with a chief complaint of weakness and change in skin color. Because of a history of alcohol consumption, the initial impression was that the patient had alcoholic hepatitis. However, the patient’s constellation of symptoms and the discovery that he was undergoing acute hemolysis provided evidence that this patient was not going to be a routine alcoholic admission. A 46-year-old Middle Eastern male presented to the ED with a several day history of weakness, dizziness, near syncope, and persistent nausea and vomiting. The patient also complained of intermittent fevers to 103°F. Additional complaints included myalgia and arthralgias of his left shoulder and lower spine. The patient had also noted that his urine had become very dark brown with episodes of hematuria. The patient’s sister had noted a change in his skin color to a yellowish hue. The patient has no significant past medical illnesses. He denied any previous history of hepatitis, hematochezia, black tarry stools, or change in his bowel movements. He denied abdominal pain. He denied any history of arthritis, malignancy, hematological problems, serious childhood illnesses, or family history of food or drug reaction. The patient’s medications were limited to Vicks’ Nyquil (Procter and Gamble, Cincinnati, OH), vitamins, and two Tylenol (McNeil Consumer Products Co, Fort Washington, PA) for his fevers. He admits to heavy consumption of alcohol at a party 3 days before his illness. The patient reports consuming large amounts of raw fava beans in addition to six to eight cocktails and many glasses of wine. He states that within 24 hours after the party, he began to feel weak, dizzy, and febrile; at the time he noted that his urine had become dark brown and intermittently bloody. His vital signs were blood pressure, 120/70 mm Hg; pulse, 104 beats/min; respirations, 18 breaths/min; and temperature, 100.6”F. On initial examination, the patient seemed to be in mild distress. The skin was jaundiced, warm, and dry; no rashes were noted. The patient was awake, alert, and fully oriented. The pupils were equal and reactive; the sclera were icteric. The fundoscopic examination was benign bilaterally. The neck was supple with no adenopathy. Examination of the heart showed a sinus tachycardia without murmur, rub, or gallop. Breath sounds were clear bilaterally with no rhonchi, tales, or wheezing. The patient’s abdomen was soft and nontender with no hepatic or splenic enlargement. Rectal examination was negative for occult blood; no masses were palpated. The prostate was normal. The extremities, neurological, and external genital examinations were within normal limits. Initial blood laboratory tests showed hemoglobin/hematocrit of 5.4/15.8; white blood cell count, 23.4; platelet count, 402. The reticulocyte count was 21%. Electrolytes were within normal limits. The blood urea nitrogen was 37 mg/dL; creatinine was 1.2 mg/dL. Liver function tests showed a total bilirubin of 7.5; alkaline phosphatase, 58; ammonia, 51; SGOT, 128; LDH, 1682. Urinalysis showed dark brown urine with no red or white blood cells. The urine specific gravity was 1.035. The patient was admitted to the intensive care unit. He was placed on 2 L of oxygen via nasal cannula, and intravenous D5 YZnormal saline was run at 150 mL/h. The patient received thiamine, multivitamins, and folic acid, as well as 2 U of blood. Gastroenterology and nephrology consultations were obtained to assist in the evaluation of the elevated liver enzymes and hematuria, respectively. The initial clinical impression by the internist was alcoholic hepatitis; alcoholic liver disease; jaundice secondary to alcoholic liver disease; acute anemia probably secondary to gastrointestinal bleeding; and hematuria of unknown etiology. 560

After appropriate consultation and complete blood panel evaluation, the etiology of the patient’s acute hemolysis and constellation of symptoms was determined to be glucose-6-phosphate dehydrogenase (G6PD) deficiency. The stimulus for initiating the hemolysis was the consumption of fava beans 24 hours before the onset of symptoms. The patient received supportive care for the next 6 days in the hospital and recovered without incident. The episode of acute hemolysis was self-limiting. The patient was discharged home after receiving educational support. The hemolytic syndrome associated with favism has been recognized since antiquity. Cordes reported the first four cases of acquired hemolytic anemia in 26 black men receiving pamaquine (an antimalarial drug) in 1926.’ In 1940, Emerson et al proposed a mechanism to explain the hemolysis of red blood cells (RBCs) by certain drugs and chemicals; substances with oxidizing activity were suggested to cause the reversible oxidation-reduction of hemoglobin to methemoglobin. In the 1950s an intrinsic defect was shown to be present in RBCs, which were hemolyzed after ingestion of pamaquine by black prison inmates. 3 Soon after, Carson et al4 determined that a lack of reduced glutathione (GSH) was a result of G6PD deficiency. G6PD deficiency is the most common disease-producing enzyme disorder of humans, with an estimated 7% of the world population carrying the gene. G6PD deficiency is inherited in a sex-linked manner; therefore, it is fully expressed in hemizygous males and homozygous females. In addition, approximately 10% of heterozygous females are affected as a result of unequal inactivation of their X-chromosomes.s A high incidence of low-activity G6PD variants is typical of the Mediterranean area and the Middle East, including the Balearic Islands, Greece, Cyprus, Turkey, Lebanon, Israel, Egypt, Northern Africa, Iran, and Iraq. Other areas include Sardinia and Sicily in Italy, and Taiwan and southern China in the Far East6 The incidence among black populations varies, with 12% of black American men reported to have the deticiency.3 The first symptoms of favism are malaise, generalized weakness to severe lethargy, nausea and vomiting, headache, and lumbar or abdominal pain. Chills, tremors, and fever are often present. Fever is inconsistent and irregular. After a delay of variable duration (a few to 48 hours), jaundice appears and may reach an intense stage. It is accompanied by enlargement of the spleen and liver. Hemoglobinuria begins several hours after fava bean intake, and may continue for several days. The lag period between intake of fava beans and outbreak of crisis is variable. During the typical crisis, jaundice is followed by anemia. Reticulocytosis is also observed. In the majority of cases, the hemolysis is self-limited. During an acute episode, the measured G6PD level may be normal: the older, G6PDdeficient cells are destroyed and replaced by a younger erythrocyte population. G6PD catalyzes the first step in the hexosemonophosphate pathway, the result of which is to reduce the cofactor nicotinamide dinucleotide phosphate (NADP) to NADPH. NADPH is necessary to protect the -SH groups of enzymes and of the B-chain of hemoglobin from oxidation. This protection is mediated by glutathione, which is present in RBCs almost entirely in the reduced form (GSH). GSH itself becomes oxidized to GSSG as it restores oxidized -SH groups. NADPH in turn regenerated GSH through the enzyme gfutathione reductase. Unlike other types of cells, RBCs do not have alternative enzyme systems that are capable of generating NADPH; therefore, in the absence of adequate G6PD activity, hemolysis is the primary effect of an oxidative stress5 It has been observed that only 10% to 20% of G6PD-deficient individuals who consume fava beans experience favic crises. In addition, an individual may be susceptible to hemolysis as a child, then

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consume fava beans for years without consequences, and later suffer from favism as an adult or in old age.6 The rate at which the oxidants are inactivated in the liver is believed to be responsible for the unpredictable nature of favism.s The admitting diagnosis of hepatic failure in this case was based on the patient’s drinking history, presenting symptoms, and jaundice, and the findings of hyperbilirubinemia and elevated serum SGOT and L.DH are consistent with this diagnosis. However, the normocytic anemia, reticulocytosis, decreased haptoglobin, hyperbilirubinemia, elevated SGOT and LDH, and hemoglobinuria are suggestive of an acute hemolytic episode. The differential diagnosis of acute hemolytic anemia is extensive. An infectious etiology was unlikely in this case because the patient was afebrile on admission; nevertheless,, blood cultures were obtained and were negative. Autoimmune hemolytic anemias (eg, caused by warm reactive antibodies or cold reactive antibodies) were ruled out with negative indirect and direct Coombs’ tests. Similarly, paroxysmal nocturnal hemoglobinuria (PNH) was ruled out with a negative sucrose hemolysis test. Traumatic hemolysis (eg, with prosthetic valves or other cardiac abnormalities) is usually suggested by the finding of schistocytes on the peripheral blood smear; they were absent in this case. Microangiopathic hemolytic anemias (eg, disseminated intravascular coagulation [DIG], thrombotic thrombocytopenic purpura [TIP], hemolytic-uremic syndrome [HUS]) are associated with RBC fragmentation on the peripheral blood smear and, in the case of TTP, thrombocytopenia. The mildly elevated platelet count, normal blood smear, and negative test for fibrin split products (for DIG) eliminated these as possible etiologies. The patient was found not to have sickle cell anemia. The patient reports eating a dish of beans which he had not eaten in ftiteen years. This history, in a patient of Middle Eastern descent, makes favism a likely cause of his hemolytic episode. A G6PD test performed on the second hospital day was normal; however, as previously mentioned, this does not exclude favism as the etiology. Because of the unpredictable nature of acute hemolytic crises in G6PD-deficient individuals, a prior uneventful history of ingestion of a known oxidant does not rule out the possibility of future hemolytic episodes. Low-grade hemolysis, weakness and pallor, light or no hemoglobinuria, and slight jaundice may require no treatment6 or only supportive therapy (ie, intravenous hydration to maintain urine output and diuresis to prevent precipitation of hemoglobin in the kidneys). However, in cases of life-threatening anemia, transfusion is the definitive treatment. The patient and his or her family should be educated in the identification and avoidance of precipitating drugs and other factors .’

5. World Health Organization Working Group: Glucose-6phosphate dehydrogenase deficiency. Bull WHO 1989;67:601611 6. Arese P, DeFlora A: Pathophysiology deficiency. Semin Hematol 1990;27:1-40

of hemolysis

in GGPD

7. Dunagan WC, Ridner ML (eds): Manual of Medical Therapeutics, ed 26. Boston, MA, Little, Brown, and Co, 1989, p 347

SAFE RIGHT SUBCLAVIAN VEIN PUNCTURE: THE IMPORTANCE OF PRESSING THE SKIN WITH THE LEFT THUMB To rhe Editor:--Infraclavicular percutaneous subclavian vein puncture for central vein access, preferably on the right side, is an essential emergency department technique that should be performed quickly and without complications. However, among the complications observed, pneumothorax is the most common initially because the apical pleura is situated approximately 5 mm behind the posterior wall of the subclavian vein after it passes over the first rib.’ Many technical guidelines regarding safe subclavian vein puncture have been published. 2,3 However, although none of these reports mention the use of the left thumb in right subclavian vein puncture. we feel it is an important procedure. Before puncture, the skin should be pressed down firmly by the left thumb placed beneath the mid-portion of the clavicle, with the index tinger pointing toward the sternal notch. In this way the target is identified (Figure I). With the skin pushed in, the needle is inserted at the caudal margin of the indentation at a point approximately 3 to 4 cm below the mid-portion of the clavicle. As long as the needle is advanced parallel to the plane of the patient’s back, the needle always enters the subclavian vein. If this technique is adopted, the frequency of accidental puncture of the apical pleura can be reduced significantly. In fact, since the introduction of this technique in our department, the frequency of pneumothorax after subclavian vein puncture has decreased dramatically. MASATAKA SHIMOTSUMA,MD NORIMASA WATANABE, MD AKIRA SAKUYAMA, MD MORIO SHIRASU, MD KAZUYA KITAMURA, MD TOSHIOTAKAHASHI, MD

Kyoto Prefectural University of Medicine Kyoto, Japan

JACQUELYN HASLER, MD STANFORD LEE, MD

University of Southern California School of Medicine Los Angeles, CA

References 1. Cordes W: Experiences with plasmaquine in malaria (Preliminary Reports). In 15th Annual Report. United Fruit Company (Medical Department), 1926, p 66-71 2. Emerson CP, Ham TH, Castle WB: Hemolytic action of certain organic oxidants derived from sulfanilamide, phenylhydrazinc, and hydroquinone. J Clin Invest 1941;20:451-454 3. O’Connell JT, Henderson AR: Glucose-g-phosphate drogenase revisited. J Nat1 Med Assoc 1984;76:1135-1136, 1143

dehy1139,

4. Carson PE, Frischer H: Glucose-6-phosphate dehydrogenase deficiency and related disorders of the pentose phosphate pathway. Am J Med 1966;41:744-761

FIGURE 1. The target is identified by pressing the skin with the left thumb beneath the mid-portion of the right clavicle. The needle is advanced parallel to the plane of the patient’s back at the caudal margin of the indented skin.