Norman Egger, MD

Adverse drug reactions are a major clinical problem, accounting for 2%-6% of all hospital admissions. And, 6%-15% of hospitalized patients experience a serious adverse drug reaction that contributes to longer hospital stays and higher costs. It is crucial for clinicians to detect, diagnose, and report adverse drug reactions to ensure safe prescribing and continued drug safety monitoring, as illustrated by this brief case presentation.

The Patient

A 72-year-old male presented to the emergency department in acute respiratory distress due to severe angioedema of the face and tongue; the patient required intubation. He denied prior episodes of angioedema. A careful evaluation of all possible causes of angioedema, including a thorough assessment of the medications used by the patient, led to the conclusion that this life-threatening incident could be attributed only to a reaction to an angiotensin-converting enzyme (ACE) inhibitor. The patient had been on ACE inhibitor therapy for hypertension for more than five years and at the time of admission had been taking a combination of benazepril and amlodipine for more than two years. This medication was immediately discontinued, and he recovered fully after five days in the ICU on mechanical ventilation.  

ACE Inhibitor-Associated Angioedema

ACE inhibitors are used by more than 35 million people worldwide to treat hypertension, heart failure, and diabetes mellitus; still, many physicians believe they are underprescribed.1 Angioedema is a serious complication of ACE inhibitor therapy that occurs in 0.1% to 0.68% of patients taking ACE inhibitors.2,3

Angioedema presents with a non-pitting swelling of subcutaneous or submucosal tissue without desquamation. Angioedema associated with ACE inhibitor use is rapid in onset, occurring minutes to hours after ingestion, does not present with urticaria, and usually lasts no more than 48 hours.4 At times, angioedema related to ACE inhibitor therapy occurs in the intestine, causing abdominal pain, diarrhea, and vomiting without mucocutaneous signs.1,4

Certain risk factors for developing ACE inhibitor-related angioedema include age older than 65, seasonal allergies, and black ethnicity. Another risk factor pertinent to our case presentation is the patient’s length of time on ACE inhibitor therapy. One study found that ACE inhibitor-associated angioedema occurred at a rate that was nine times higher during the first month of therapy than during subsequent months of therapy.2 Agostoni and colleagues found that ACE inhibitor-associated angioedema could occur in patients who had been on ACE inhibitor therapy for as long as eight years.5

The Process

ACE inhibitor-induced angioedema is probably a multifactorial process. Angiotensin-converting enzyme (ACE) metabolizes angiotensin I to angiotensin II in vivo and is a major inactivator of bradykinin. ACE and aminopeptidase P are the major pathways of bradykinin metabolism. A minor pathway uses carboxypeptidase N, which metabolizes bradykinin to its active metabolite, des-Arg-bradykinin. Des-Arg-bradykinin can then be inactivated by ACE and aminopeptidase P. In patients who had angioedema caused by ACE inhibitors, higher levels of des-Arg-bradykinin were found due to decreased activity of aminopeptidase P, which normally plays a major role in bradykinin breakdown when an ACE inhibitor is present.6

Bradykinin is a beta2 receptor agonist, but, when it is metabolized by carboxypeptidase N to des-Arg-bradykinin, it becomes a beta1 receptor agonist.6

During ACE inhibitor therapy, bradykinin can be inactivated by aminopeptidase P or metabolized into a beta1 receptor agonist by carboxypeptidase N, which is then broken down by aminopeptidase P. If aminopeptidase P is not active, then bradykinin can be converted to des-Arg-bradykinin, which can then act on upregulated beta1 receptors in the oropharynx and tongue, producing vasodilation, increased capillary permeability, and pain.

Treatment

Treatment of ACE inhibitor-induced angioedema includes discontinuing the ACE inhibitor and providing symptomatic support. Although some ACE inhibitors are more likely than others to cause angioedema, a patient who has had an episode of ACE inhibitor-associated angioedema should never again use any ACE inhibitor.3 Angiotensin receptor blockers (ARBs) do not affect the bradykinin system; however, they can cause angioedema (0.13% in one trial of ARBs), and it is not known if ARBs should be avoided in patients who have had ACE inhibitor-induced angioedema.7 Therapy with a bradykinin receptor antagonist to prevent or resolve ACE inhibitor-associated angioedema has not yet been studied in detail.1

Summary

Adverse drug reactions can present clinically in many different ways, and, indeed, these reactions have deposed syphilis and tuberculosis as the mimic of disease. Many adverse drug reactions are mild, but others can be severe and, occasionally, life-threatening. This variability in manifestations means clinicians always have to consider that the drug may be the cause of the patient’s symptoms. TH

Johnson is a medical student at the Kansas City University of Medicine and Biosciences, Kansas City, Mo. Dr. Egger is a consultant in general internal medicine at the Mayo Clinic, Rochester, Minn.

References

1. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737.
2. Kostis JB, Kim HJ, Rusnak J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005 Jul;165(14):1637-1642.
3. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004 Feb;17(2):103-111.
4. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53:373-388.
5. Agostoni A, Cicardi M, Cugno M, et al. Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology. 1999;44:21-25.
6. Molinaro G, Cugno M, Perez M, et al. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther. 2002;303:232-237.
7. Ward KE, Hume AL. Olmesartan (benicar) for hypertension. Am Fam Physician. 2005;72:673-674.

Adverse drug reactions are a major clinical problem, accounting for 2%-6% of all hospital admissions. And, 6%-15% of hospitalized patients experience a serious adverse drug reaction that contributes to longer hospital stays and higher costs. It is crucial for clinicians to detect, diagnose, and report adverse drug reactions to ensure safe prescribing and continued drug safety monitoring, as illustrated by this brief case presentation.

The Patient

A 72-year-old male presented to the emergency department in acute respiratory distress due to severe angioedema of the face and tongue; the patient required intubation. He denied prior episodes of angioedema. A careful evaluation of all possible causes of angioedema, including a thorough assessment of the medications used by the patient, led to the conclusion that this life-threatening incident could be attributed only to a reaction to an angiotensin-converting enzyme (ACE) inhibitor. The patient had been on ACE inhibitor therapy for hypertension for more than five years and at the time of admission had been taking a combination of benazepril and amlodipine for more than two years. This medication was immediately discontinued, and he recovered fully after five days in the ICU on mechanical ventilation.  

ACE Inhibitor-Associated Angioedema

ACE inhibitors are used by more than 35 million people worldwide to treat hypertension, heart failure, and diabetes mellitus; still, many physicians believe they are underprescribed.1 Angioedema is a serious complication of ACE inhibitor therapy that occurs in 0.1% to 0.68% of patients taking ACE inhibitors.2,3

Angioedema presents with a non-pitting swelling of subcutaneous or submucosal tissue without desquamation. Angioedema associated with ACE inhibitor use is rapid in onset, occurring minutes to hours after ingestion, does not present with urticaria, and usually lasts no more than 48 hours.4 At times, angioedema related to ACE inhibitor therapy occurs in the intestine, causing abdominal pain, diarrhea, and vomiting without mucocutaneous signs.1,4

Certain risk factors for developing ACE inhibitor-related angioedema include age older than 65, seasonal allergies, and black ethnicity. Another risk factor pertinent to our case presentation is the patient’s length of time on ACE inhibitor therapy. One study found that ACE inhibitor-associated angioedema occurred at a rate that was nine times higher during the first month of therapy than during subsequent months of therapy.2 Agostoni and colleagues found that ACE inhibitor-associated angioedema could occur in patients who had been on ACE inhibitor therapy for as long as eight years.5

The Process

ACE inhibitor-induced angioedema is probably a multifactorial process. Angiotensin-converting enzyme (ACE) metabolizes angiotensin I to angiotensin II in vivo and is a major inactivator of bradykinin. ACE and aminopeptidase P are the major pathways of bradykinin metabolism. A minor pathway uses carboxypeptidase N, which metabolizes bradykinin to its active metabolite, des-Arg-bradykinin. Des-Arg-bradykinin can then be inactivated by ACE and aminopeptidase P. In patients who had angioedema caused by ACE inhibitors, higher levels of des-Arg-bradykinin were found due to decreased activity of aminopeptidase P, which normally plays a major role in bradykinin breakdown when an ACE inhibitor is present.6

Bradykinin is a beta2 receptor agonist, but, when it is metabolized by carboxypeptidase N to des-Arg-bradykinin, it becomes a beta1 receptor agonist.6

During ACE inhibitor therapy, bradykinin can be inactivated by aminopeptidase P or metabolized into a beta1 receptor agonist by carboxypeptidase N, which is then broken down by aminopeptidase P. If aminopeptidase P is not active, then bradykinin can be converted to des-Arg-bradykinin, which can then act on upregulated beta1 receptors in the oropharynx and tongue, producing vasodilation, increased capillary permeability, and pain.

Treatment

Treatment of ACE inhibitor-induced angioedema includes discontinuing the ACE inhibitor and providing symptomatic support. Although some ACE inhibitors are more likely than others to cause angioedema, a patient who has had an episode of ACE inhibitor-associated angioedema should never again use any ACE inhibitor.3 Angiotensin receptor blockers (ARBs) do not affect the bradykinin system; however, they can cause angioedema (0.13% in one trial of ARBs), and it is not known if ARBs should be avoided in patients who have had ACE inhibitor-induced angioedema.7 Therapy with a bradykinin receptor antagonist to prevent or resolve ACE inhibitor-associated angioedema has not yet been studied in detail.1

Summary

Adverse drug reactions can present clinically in many different ways, and, indeed, these reactions have deposed syphilis and tuberculosis as the mimic of disease. Many adverse drug reactions are mild, but others can be severe and, occasionally, life-threatening. This variability in manifestations means clinicians always have to consider that the drug may be the cause of the patient’s symptoms. TH

Johnson is a medical student at the Kansas City University of Medicine and Biosciences, Kansas City, Mo. Dr. Egger is a consultant in general internal medicine at the Mayo Clinic, Rochester, Minn.

References

1. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737.
2. Kostis JB, Kim HJ, Rusnak J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005 Jul;165(14):1637-1642.
3. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004 Feb;17(2):103-111.
4. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53:373-388.
5. Agostoni A, Cicardi M, Cugno M, et al. Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology. 1999;44:21-25.
6. Molinaro G, Cugno M, Perez M, et al. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther. 2002;303:232-237.
7. Ward KE, Hume AL. Olmesartan (benicar) for hypertension. Am Fam Physician. 2005;72:673-674.

Adverse drug reactions are a major clinical problem, accounting for 2%-6% of all hospital admissions. And, 6%-15% of hospitalized patients experience a serious adverse drug reaction that contributes to longer hospital stays and higher costs. It is crucial for clinicians to detect, diagnose, and report adverse drug reactions to ensure safe prescribing and continued drug safety monitoring, as illustrated by this brief case presentation.

The Patient

A 72-year-old male presented to the emergency department in acute respiratory distress due to severe angioedema of the face and tongue; the patient required intubation. He denied prior episodes of angioedema. A careful evaluation of all possible causes of angioedema, including a thorough assessment of the medications used by the patient, led to the conclusion that this life-threatening incident could be attributed only to a reaction to an angiotensin-converting enzyme (ACE) inhibitor. The patient had been on ACE inhibitor therapy for hypertension for more than five years and at the time of admission had been taking a combination of benazepril and amlodipine for more than two years. This medication was immediately discontinued, and he recovered fully after five days in the ICU on mechanical ventilation.  

ACE Inhibitor-Associated Angioedema

ACE inhibitors are used by more than 35 million people worldwide to treat hypertension, heart failure, and diabetes mellitus; still, many physicians believe they are underprescribed.1 Angioedema is a serious complication of ACE inhibitor therapy that occurs in 0.1% to 0.68% of patients taking ACE inhibitors.2,3

Angioedema presents with a non-pitting swelling of subcutaneous or submucosal tissue without desquamation. Angioedema associated with ACE inhibitor use is rapid in onset, occurring minutes to hours after ingestion, does not present with urticaria, and usually lasts no more than 48 hours.4 At times, angioedema related to ACE inhibitor therapy occurs in the intestine, causing abdominal pain, diarrhea, and vomiting without mucocutaneous signs.1,4

Certain risk factors for developing ACE inhibitor-related angioedema include age older than 65, seasonal allergies, and black ethnicity. Another risk factor pertinent to our case presentation is the patient’s length of time on ACE inhibitor therapy. One study found that ACE inhibitor-associated angioedema occurred at a rate that was nine times higher during the first month of therapy than during subsequent months of therapy.2 Agostoni and colleagues found that ACE inhibitor-associated angioedema could occur in patients who had been on ACE inhibitor therapy for as long as eight years.5

The Process

ACE inhibitor-induced angioedema is probably a multifactorial process. Angiotensin-converting enzyme (ACE) metabolizes angiotensin I to angiotensin II in vivo and is a major inactivator of bradykinin. ACE and aminopeptidase P are the major pathways of bradykinin metabolism. A minor pathway uses carboxypeptidase N, which metabolizes bradykinin to its active metabolite, des-Arg-bradykinin. Des-Arg-bradykinin can then be inactivated by ACE and aminopeptidase P. In patients who had angioedema caused by ACE inhibitors, higher levels of des-Arg-bradykinin were found due to decreased activity of aminopeptidase P, which normally plays a major role in bradykinin breakdown when an ACE inhibitor is present.6

Bradykinin is a beta2 receptor agonist, but, when it is metabolized by carboxypeptidase N to des-Arg-bradykinin, it becomes a beta1 receptor agonist.6

During ACE inhibitor therapy, bradykinin can be inactivated by aminopeptidase P or metabolized into a beta1 receptor agonist by carboxypeptidase N, which is then broken down by aminopeptidase P. If aminopeptidase P is not active, then bradykinin can be converted to des-Arg-bradykinin, which can then act on upregulated beta1 receptors in the oropharynx and tongue, producing vasodilation, increased capillary permeability, and pain.

Treatment

Treatment of ACE inhibitor-induced angioedema includes discontinuing the ACE inhibitor and providing symptomatic support. Although some ACE inhibitors are more likely than others to cause angioedema, a patient who has had an episode of ACE inhibitor-associated angioedema should never again use any ACE inhibitor.3 Angiotensin receptor blockers (ARBs) do not affect the bradykinin system; however, they can cause angioedema (0.13% in one trial of ARBs), and it is not known if ARBs should be avoided in patients who have had ACE inhibitor-induced angioedema.7 Therapy with a bradykinin receptor antagonist to prevent or resolve ACE inhibitor-associated angioedema has not yet been studied in detail.1

Summary

Adverse drug reactions can present clinically in many different ways, and, indeed, these reactions have deposed syphilis and tuberculosis as the mimic of disease. Many adverse drug reactions are mild, but others can be severe and, occasionally, life-threatening. This variability in manifestations means clinicians always have to consider that the drug may be the cause of the patient’s symptoms. TH

Johnson is a medical student at the Kansas City University of Medicine and Biosciences, Kansas City, Mo. Dr. Egger is a consultant in general internal medicine at the Mayo Clinic, Rochester, Minn.

References

1. Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006;26(4):725-737.
2. Kostis JB, Kim HJ, Rusnak J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005 Jul;165(14):1637-1642.
3. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004 Feb;17(2):103-111.
4. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53:373-388.
5. Agostoni A, Cicardi M, Cugno M, et al. Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology. 1999;44:21-25.
6. Molinaro G, Cugno M, Perez M, et al. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. J Pharmacol Exp Ther. 2002;303:232-237.
7. Ward KE, Hume AL. Olmesartan (benicar) for hypertension. Am Fam Physician. 2005;72:673-674.

What do the Japanese military, a Dutch microbiologist, sick chickens, and rice polishers have in common?

In the 1800s, Europeans colonizing Asia brought with them steam-powered machines that completely polished rice. This rice, which was thought to be superior to unpolished rice, became very popular. As Far Eastern society’s main source of thiamine was polished to oblivion, beriberi became more prevalent and problematic.

At that time, micronutrient deficiency states were still a mystery to physicians. Kanehiro Takaki (October 30, 1849–April 13, 1920), surgeon general of the Japanese Imperial Navy, noticed a connection between sailors’ diets and their development of beriberi. White rice was replaced with barley, vegetables, fish, and meat. The incidence of beriberi dropped swiftly and was eliminated in the Japanese Navy, within six years.

Kanehiro Takaki

Meanwhile, in the Dutch Indies, beriberi was endemic and crippling. Christiaan Eijkman, a Dutch microbiologist (August 11, 1858–November 5, 1930) who had studied with bacteriologist Robert Koch (December 11, 1843-May 27, 1910) in Berlin, was sent to research the disease in Java. Eijkman was unaware of Takaki’s findings and was convinced that beriberi was an infection.

Eijkman tried to infect chickens with a microorganism isolated from the corpses of two beriberi-related deaths. While he was striving to find the causative pathogen, Eijkman noticed that all chickens, even those having no contact with either the microorganism or other chickens, developed “a disease, in many respects strikingly similar to beriberi in man.” In fact, they had developed polyneuritis. Then, miraculously, they recovered spontaneously.

Christiaan Eijkman

Eijkman was bewildered by this sequence of events and set out to solve the poultry mystery. He discovered that the chickens, during the time that they had been ill, had been eating leftover cooked, polished white rice from the hospital kitchen. When the cook left, however, his replacement refused to relinquish leftover rice, and they were thereafter given raw, unpolished rice. After this dietary change, the chickens recovered. Eijkman concluded that a substance in unpolished rice protected chickens against infection—he was still searching for the elusive microscopic culprit—and he called this protective substance the “anti-beriberi factor.” He thought unpolished rice contained an antidote to a bacterial toxin.

In 1906, Frederick Hopkins (1861–1947) demonstrated “accessory factors” in food, those nutrients necessary to maintain good health in addition to the carbohydrates, fats, proteins, and minerals that had previously been acknowledged as vital. In 1912, a Polish biochemist, Casimir Funk (1884–1967), thought he had isolated the anti-beriberi factor and named his discovery vitamine, from “vital amine.” Although he hadn’t isolated anti-beriberi factor—it is believed that he isolated nicotinic acid—the name vitamine remained. Eventually, in 1926, researchers were able to isolate the anti-beriberi factor in rice bran extracts. In 1929, Hopkins and Eijkman were awarded the Nobel Prize in Physiology or Medicine for the discovery of vitamins.

Frederick Hopkins

Clinicians are now well aware of alcohol abuse and the development of Wernicke’s encephalopathy or Korsakoff amnestic syndrome. Phrases like wet (high output heart failure) and dry (peripheral neuropathy) beriberi were once commonly found on board exams. The clinical presentation of thiamine deficiency isn’t limited to alcoholics. For example, there is evidence that patients with end-stage renal disease on hemodialysis are at risk of becoming thiamine deficient and of developing “unexplained” encephalopathies.1 Patients who suffer congestive heart failure while on long-term diuretics are also at increased risk for thiamine deficiency.2

This account is a classic example of the fascinating way in which the discovery of these essential nutrients has evolved and serves as a wake-up call that emphasizes the current epidemic of malnutrition in hospitalized patients.

Protein energy malnutrition in hospitalized patients is very common. Many studies have demonstrated that the prevalence runs between 30% and 60%, depending on the patient population studied and the assessment tools used. Hospital malnutrition, independent of disease activity, has been linked to increased length of stay and heightened morbidity and mortality. It is disturbing to think that many patients are actually worse off at time of dismissal than they were at admission. Malnutrition often goes unrecognized and even when the problem is acknowledged adequate nutrition is often not provided. Patients are commonly permitted to subsist on very low nutrient intakes.3 The problem of malnutrition is likely grossly underestimated because most studies have not considered micronutrients such as trace elements and vitamins. In addition, the presence of subclinical, yet clinically important, deficiency is expected to be highly prevalent.

Early screening improves the recognition of malnourished patients and provides the opportunity to start treatment at an early stage of hospitalization. Nutritional therapy as part of a comprehensive treatment modality may result in improvement of healthcare quality. In some countries it is also a criterion for assessing the performance of hospitals. In the U.S., for example, nutritional screening in hospitals is required for accreditation by the Joint Commission on Accreditation of Healthcare Organizations and is part of the Minimal Data Set documentation in long-term care facilities.

In most institutions, nutritional screening refers to a rapid and general test that is undertaken by nursing, medical, and other staff, often at first contact with patients. This is in contrast to the detailed nutritional evaluation that is undertaken by nutrition specialists (e.g., dietitians, specialist nutrition nurses, or physicians with an interest in nutrition), often for complex problems and often following nutritional screening. The introduction of a nutrition screening program and documentation of nutritional status may also increase diagnosis-related group (DRG)-based reimbursement.

Unfortunately, a lack of standardized sensitive and specific methodologies to assess for macro- or micronutrient deficiencies makes it difficult to determine how best to screen patients. Recent literature suggests, however, that the use of a short nutrition questionnaire and an undemanding treatment plan improved nutritional care during a hospital stay.4 The use of this strategy reduced the duration of the hospital stay in a subgroup of frail malnourished patients, offering potential improvements in morbidity as well as financial benefits for the hospital.

The lessons of past discoveries should not be lost on modern medicine. Malnutrition can be made a condition of the past through the use of simple screening procedures and uncomplicated treatments. The results will benefit both patients and hospitals. TH

Michelle Schneider is a medical student at the Royal College of Surgeons in Dublin, Ireland. Dr. Egger is a senior associate consultant at the Mayo Clinic College of Medicine.

References

1. Hung SC, Hung SH, Tarng DC, et al. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 2001;38:941-947.
2. Hanninen SA, Darling PB, Sole MJ, et al. The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol. 2006 Jan 17;47(2):354-361.
3. Sullivan DH, Sun S, Walls RC. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. JAMA. 1999 Jun;281(21):2013-2019.
4. Kruizenga HM, Van Tulder MW, Seidell JC, et al. Effectiveness and cost-effectiveness of early screening and treatment of malnourished patients. Am J Clin Nutr. 2005;82(5):1082-1089.

What do the Japanese military, a Dutch microbiologist, sick chickens, and rice polishers have in common?

In the 1800s, Europeans colonizing Asia brought with them steam-powered machines that completely polished rice. This rice, which was thought to be superior to unpolished rice, became very popular. As Far Eastern society’s main source of thiamine was polished to oblivion, beriberi became more prevalent and problematic.

At that time, micronutrient deficiency states were still a mystery to physicians. Kanehiro Takaki (October 30, 1849–April 13, 1920), surgeon general of the Japanese Imperial Navy, noticed a connection between sailors’ diets and their development of beriberi. White rice was replaced with barley, vegetables, fish, and meat. The incidence of beriberi dropped swiftly and was eliminated in the Japanese Navy, within six years.

Kanehiro Takaki

Meanwhile, in the Dutch Indies, beriberi was endemic and crippling. Christiaan Eijkman, a Dutch microbiologist (August 11, 1858–November 5, 1930) who had studied with bacteriologist Robert Koch (December 11, 1843-May 27, 1910) in Berlin, was sent to research the disease in Java. Eijkman was unaware of Takaki’s findings and was convinced that beriberi was an infection.

Eijkman tried to infect chickens with a microorganism isolated from the corpses of two beriberi-related deaths. While he was striving to find the causative pathogen, Eijkman noticed that all chickens, even those having no contact with either the microorganism or other chickens, developed “a disease, in many respects strikingly similar to beriberi in man.” In fact, they had developed polyneuritis. Then, miraculously, they recovered spontaneously.

Christiaan Eijkman

Eijkman was bewildered by this sequence of events and set out to solve the poultry mystery. He discovered that the chickens, during the time that they had been ill, had been eating leftover cooked, polished white rice from the hospital kitchen. When the cook left, however, his replacement refused to relinquish leftover rice, and they were thereafter given raw, unpolished rice. After this dietary change, the chickens recovered. Eijkman concluded that a substance in unpolished rice protected chickens against infection—he was still searching for the elusive microscopic culprit—and he called this protective substance the “anti-beriberi factor.” He thought unpolished rice contained an antidote to a bacterial toxin.

In 1906, Frederick Hopkins (1861–1947) demonstrated “accessory factors” in food, those nutrients necessary to maintain good health in addition to the carbohydrates, fats, proteins, and minerals that had previously been acknowledged as vital. In 1912, a Polish biochemist, Casimir Funk (1884–1967), thought he had isolated the anti-beriberi factor and named his discovery vitamine, from “vital amine.” Although he hadn’t isolated anti-beriberi factor—it is believed that he isolated nicotinic acid—the name vitamine remained. Eventually, in 1926, researchers were able to isolate the anti-beriberi factor in rice bran extracts. In 1929, Hopkins and Eijkman were awarded the Nobel Prize in Physiology or Medicine for the discovery of vitamins.

Frederick Hopkins

Clinicians are now well aware of alcohol abuse and the development of Wernicke’s encephalopathy or Korsakoff amnestic syndrome. Phrases like wet (high output heart failure) and dry (peripheral neuropathy) beriberi were once commonly found on board exams. The clinical presentation of thiamine deficiency isn’t limited to alcoholics. For example, there is evidence that patients with end-stage renal disease on hemodialysis are at risk of becoming thiamine deficient and of developing “unexplained” encephalopathies.1 Patients who suffer congestive heart failure while on long-term diuretics are also at increased risk for thiamine deficiency.2

This account is a classic example of the fascinating way in which the discovery of these essential nutrients has evolved and serves as a wake-up call that emphasizes the current epidemic of malnutrition in hospitalized patients.

Protein energy malnutrition in hospitalized patients is very common. Many studies have demonstrated that the prevalence runs between 30% and 60%, depending on the patient population studied and the assessment tools used. Hospital malnutrition, independent of disease activity, has been linked to increased length of stay and heightened morbidity and mortality. It is disturbing to think that many patients are actually worse off at time of dismissal than they were at admission. Malnutrition often goes unrecognized and even when the problem is acknowledged adequate nutrition is often not provided. Patients are commonly permitted to subsist on very low nutrient intakes.3 The problem of malnutrition is likely grossly underestimated because most studies have not considered micronutrients such as trace elements and vitamins. In addition, the presence of subclinical, yet clinically important, deficiency is expected to be highly prevalent.

Early screening improves the recognition of malnourished patients and provides the opportunity to start treatment at an early stage of hospitalization. Nutritional therapy as part of a comprehensive treatment modality may result in improvement of healthcare quality. In some countries it is also a criterion for assessing the performance of hospitals. In the U.S., for example, nutritional screening in hospitals is required for accreditation by the Joint Commission on Accreditation of Healthcare Organizations and is part of the Minimal Data Set documentation in long-term care facilities.

In most institutions, nutritional screening refers to a rapid and general test that is undertaken by nursing, medical, and other staff, often at first contact with patients. This is in contrast to the detailed nutritional evaluation that is undertaken by nutrition specialists (e.g., dietitians, specialist nutrition nurses, or physicians with an interest in nutrition), often for complex problems and often following nutritional screening. The introduction of a nutrition screening program and documentation of nutritional status may also increase diagnosis-related group (DRG)-based reimbursement.

Unfortunately, a lack of standardized sensitive and specific methodologies to assess for macro- or micronutrient deficiencies makes it difficult to determine how best to screen patients. Recent literature suggests, however, that the use of a short nutrition questionnaire and an undemanding treatment plan improved nutritional care during a hospital stay.4 The use of this strategy reduced the duration of the hospital stay in a subgroup of frail malnourished patients, offering potential improvements in morbidity as well as financial benefits for the hospital.

The lessons of past discoveries should not be lost on modern medicine. Malnutrition can be made a condition of the past through the use of simple screening procedures and uncomplicated treatments. The results will benefit both patients and hospitals. TH

Michelle Schneider is a medical student at the Royal College of Surgeons in Dublin, Ireland. Dr. Egger is a senior associate consultant at the Mayo Clinic College of Medicine.

References

1. Hung SC, Hung SH, Tarng DC, et al. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 2001;38:941-947.
2. Hanninen SA, Darling PB, Sole MJ, et al. The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol. 2006 Jan 17;47(2):354-361.
3. Sullivan DH, Sun S, Walls RC. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. JAMA. 1999 Jun;281(21):2013-2019.
4. Kruizenga HM, Van Tulder MW, Seidell JC, et al. Effectiveness and cost-effectiveness of early screening and treatment of malnourished patients. Am J Clin Nutr. 2005;82(5):1082-1089.

What do the Japanese military, a Dutch microbiologist, sick chickens, and rice polishers have in common?

In the 1800s, Europeans colonizing Asia brought with them steam-powered machines that completely polished rice. This rice, which was thought to be superior to unpolished rice, became very popular. As Far Eastern society’s main source of thiamine was polished to oblivion, beriberi became more prevalent and problematic.

At that time, micronutrient deficiency states were still a mystery to physicians. Kanehiro Takaki (October 30, 1849–April 13, 1920), surgeon general of the Japanese Imperial Navy, noticed a connection between sailors’ diets and their development of beriberi. White rice was replaced with barley, vegetables, fish, and meat. The incidence of beriberi dropped swiftly and was eliminated in the Japanese Navy, within six years.

Kanehiro Takaki

Meanwhile, in the Dutch Indies, beriberi was endemic and crippling. Christiaan Eijkman, a Dutch microbiologist (August 11, 1858–November 5, 1930) who had studied with bacteriologist Robert Koch (December 11, 1843-May 27, 1910) in Berlin, was sent to research the disease in Java. Eijkman was unaware of Takaki’s findings and was convinced that beriberi was an infection.

Eijkman tried to infect chickens with a microorganism isolated from the corpses of two beriberi-related deaths. While he was striving to find the causative pathogen, Eijkman noticed that all chickens, even those having no contact with either the microorganism or other chickens, developed “a disease, in many respects strikingly similar to beriberi in man.” In fact, they had developed polyneuritis. Then, miraculously, they recovered spontaneously.

Christiaan Eijkman

Eijkman was bewildered by this sequence of events and set out to solve the poultry mystery. He discovered that the chickens, during the time that they had been ill, had been eating leftover cooked, polished white rice from the hospital kitchen. When the cook left, however, his replacement refused to relinquish leftover rice, and they were thereafter given raw, unpolished rice. After this dietary change, the chickens recovered. Eijkman concluded that a substance in unpolished rice protected chickens against infection—he was still searching for the elusive microscopic culprit—and he called this protective substance the “anti-beriberi factor.” He thought unpolished rice contained an antidote to a bacterial toxin.

In 1906, Frederick Hopkins (1861–1947) demonstrated “accessory factors” in food, those nutrients necessary to maintain good health in addition to the carbohydrates, fats, proteins, and minerals that had previously been acknowledged as vital. In 1912, a Polish biochemist, Casimir Funk (1884–1967), thought he had isolated the anti-beriberi factor and named his discovery vitamine, from “vital amine.” Although he hadn’t isolated anti-beriberi factor—it is believed that he isolated nicotinic acid—the name vitamine remained. Eventually, in 1926, researchers were able to isolate the anti-beriberi factor in rice bran extracts. In 1929, Hopkins and Eijkman were awarded the Nobel Prize in Physiology or Medicine for the discovery of vitamins.

Frederick Hopkins

Clinicians are now well aware of alcohol abuse and the development of Wernicke’s encephalopathy or Korsakoff amnestic syndrome. Phrases like wet (high output heart failure) and dry (peripheral neuropathy) beriberi were once commonly found on board exams. The clinical presentation of thiamine deficiency isn’t limited to alcoholics. For example, there is evidence that patients with end-stage renal disease on hemodialysis are at risk of becoming thiamine deficient and of developing “unexplained” encephalopathies.1 Patients who suffer congestive heart failure while on long-term diuretics are also at increased risk for thiamine deficiency.2

This account is a classic example of the fascinating way in which the discovery of these essential nutrients has evolved and serves as a wake-up call that emphasizes the current epidemic of malnutrition in hospitalized patients.

Protein energy malnutrition in hospitalized patients is very common. Many studies have demonstrated that the prevalence runs between 30% and 60%, depending on the patient population studied and the assessment tools used. Hospital malnutrition, independent of disease activity, has been linked to increased length of stay and heightened morbidity and mortality. It is disturbing to think that many patients are actually worse off at time of dismissal than they were at admission. Malnutrition often goes unrecognized and even when the problem is acknowledged adequate nutrition is often not provided. Patients are commonly permitted to subsist on very low nutrient intakes.3 The problem of malnutrition is likely grossly underestimated because most studies have not considered micronutrients such as trace elements and vitamins. In addition, the presence of subclinical, yet clinically important, deficiency is expected to be highly prevalent.

Early screening improves the recognition of malnourished patients and provides the opportunity to start treatment at an early stage of hospitalization. Nutritional therapy as part of a comprehensive treatment modality may result in improvement of healthcare quality. In some countries it is also a criterion for assessing the performance of hospitals. In the U.S., for example, nutritional screening in hospitals is required for accreditation by the Joint Commission on Accreditation of Healthcare Organizations and is part of the Minimal Data Set documentation in long-term care facilities.

In most institutions, nutritional screening refers to a rapid and general test that is undertaken by nursing, medical, and other staff, often at first contact with patients. This is in contrast to the detailed nutritional evaluation that is undertaken by nutrition specialists (e.g., dietitians, specialist nutrition nurses, or physicians with an interest in nutrition), often for complex problems and often following nutritional screening. The introduction of a nutrition screening program and documentation of nutritional status may also increase diagnosis-related group (DRG)-based reimbursement.

Unfortunately, a lack of standardized sensitive and specific methodologies to assess for macro- or micronutrient deficiencies makes it difficult to determine how best to screen patients. Recent literature suggests, however, that the use of a short nutrition questionnaire and an undemanding treatment plan improved nutritional care during a hospital stay.4 The use of this strategy reduced the duration of the hospital stay in a subgroup of frail malnourished patients, offering potential improvements in morbidity as well as financial benefits for the hospital.

The lessons of past discoveries should not be lost on modern medicine. Malnutrition can be made a condition of the past through the use of simple screening procedures and uncomplicated treatments. The results will benefit both patients and hospitals. TH

Michelle Schneider is a medical student at the Royal College of Surgeons in Dublin, Ireland. Dr. Egger is a senior associate consultant at the Mayo Clinic College of Medicine.

References

1. Hung SC, Hung SH, Tarng DC, et al. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 2001;38:941-947.
2. Hanninen SA, Darling PB, Sole MJ, et al. The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol. 2006 Jan 17;47(2):354-361.
3. Sullivan DH, Sun S, Walls RC. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. JAMA. 1999 Jun;281(21):2013-2019.
4. Kruizenga HM, Van Tulder MW, Seidell JC, et al. Effectiveness and cost-effectiveness of early screening and treatment of malnourished patients. Am J Clin Nutr. 2005;82(5):1082-1089.