Vol.

333

No. 25

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

1695

CASE RECORDS
OF THE

Table 1. Hematologic Laboratory Values.

VARIABLE VALUE

MASSACHUSETTS GENERAL HOSPITAL

Weekly Clinicopathological Exercises

FOUNDED BY RICHARD C . CABOT

Hematocrit (%) Mean corpuscular volume (mm3) Reticulocyte count (%)* White-cell count (per mm3) Differential count (%) Neutrophils Lymphocytes Monocytes Erythrocyte sedimentation rate (mm/hr) Platelet count (per mm3) Prothrombin time (sec) Partial-thromboplastin time (sec)

23.7 98 4.1 8,100 87 8 5 65 248,000 11 (control value, 10.3) 21

ROBERT E. SCULLY, M.D., Editor EUGENE J. MARK, M.D., Associate Editor WILLIAM F. MCNEELY, M.D., Associate Editor BETTY U. MCNEELY, Assistant Editor
Table 2. Blood Chemical Findings.*
*There was no evidence of hemolysis on the peripheral-blood smear.

Mrs. Betty U. McNeely, assistant editor of the Case Records of the Massachusetts General Hospital for the past 38 years, died October 1, 1995. During her tenure she painstakingly organized and skillfully edited approximately 2000 cases. She will be greatly missed by her associates and her extended family of readers. CASE 39-1995 PRESENTATION
OF

VARIABLE

ON ADMISSION

DAY 2

DAY 11

DAY 16

CASE

A 72-year-old man was admitted to the hospital because of exertional dyspnea, fatigue, and extensive ecchymoses and purpuric lesions. During the preceding six months he had been followed as an outpatient because of anorexia, persistent exertional dyspnea, frontal headache, apathy, and irritability, which were not relieved by antidepressant medication. One month before admission he began to have increasing anorexia, with nausea and an unsteady gait, followed by the development of bruises on the left leg and abdomen. Several days before admission the dyspnea began to worsen, with lightheadedness and increasing fatigue. On the day of admission a neighbor found the patient too weak to arise from bed, and he was brought to the hospital. The patient was a retired administrator. He was a chronic alcoholic, had been divorced twice, and lived alone; he did not smoke. He reported that he was bisexual but had not had any sexual contacts for 10 years. There was a history of severe hepatitis 20 years earlier. He had a long history of hypertension, for which he took enalapril and verapamil. There was no history of trauma, fever, chills, cough, hemoptysis, hematemesis, hematochezia, melena, bleeding from the gums, abdominal pain, a change in bowel habits, or weight loss. The temperature was 36.8 C, the pulse was 75, and the respirations were 30. The blood pressure was 160/80 mm Hg.

Urea nitrogen (mg/dl) Creatinine (mg/dl) Protein (g/dl) Albumin Globulin Sodium (mmol/liter) Potassium (mmol/liter) Chloride (mmol/liter) Carbon dioxide (mmol/liter) Magnesium (mmol/liter) Lactic acid (mmol/liter) Bilirubin (mg/dl) Total Conjugated Calcium (mg/dl) Phosphorus (mg/dl) Glucose (mg/dl) Iron (mg/dl) Iron-binding capacity, total (mg/dl) Haptoglobin (mg/dl) Folic acid Vitamin B12 Ammonia Alkaline phosphatase (U/liter) Lactate dehydrogenase (U/liter) Aspartate aminotransferase (U/liter) Alanine aminotransferase Creatine kinase

30 1.7 5.3 2.0 3.3 141 3.7 107 19 0.6 1.7 5 2.1 7.7 2.7 131 96 248 185 Normal Normal Normal 154 324 51 Normal Normal 6.8 3.8

12 1.4

1.8 0.8

217 30

*To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the value for magnesium to milliequivalents per liter, divide by 0.5. To convert values for total and conjugated bilirubin to micromoles per liter, multiply by 17.1. To convert the value for calcium to millimoles per liter, multiply by 0.25. To convert the value for phosphorus to millimoles per liter, multiply by 0.3229. To convert the value for glucose to millimoles per liter, multiply by 0.05551. To convert the values for iron and total iron-binding capacity to micromoles per liter, multiply by 0.1791. Normal range, 13 to 162 mg per deciliter.

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

1696

THE NEW ENGLAND JOURNAL OF MEDICINE

Dec. 21, 1995

On physical examination the patient was obese and mildly icteric and appeared weak. Conuent purpuric plaques extended from the left ankle to above the knee; less conuent purpuric plaques and nodules were observed on the right leg, perineum, scrotum, abdomen, anks, and back. No lesions were observed on the hands, feet, or nail beds. One or two of the larger plaques were tender to touch. No petechiae were seen, and no lymphadenopathy was found. A hemorrhagic, violaceous nodule, 1 cm in diameter, was present on the lower gingiva; there was evidence of poor oral hygiene and periodontal disease. The neck, lungs, and heart were normal. The liver edge descended 4 cm below the right costal margin; the spleen was not felt. There was peripheral edema. Rectal examination revealed a normal prostate gland, and a stool specimen was positive for occult blood. The deep tendon reexes were in the arms and absent in the legs. The urine was positive for protein (trace) and for ketones, bile, and urobilinogen (); the sediment contained 1 red cell, 15 white cells, and moderate numbers of granular casts and bacteria per high-power eld. Laboratory studies were performed (Tables 1, 2, and 3). An electrocardiogram showed a normal rhythm at a rate of 90, with occasional premature ventricular contractions, a prolonged QTc interval, evidence of an inferior myocardial infarct of uncertain age, and inverted T waves in leads that reected the anterior and lateral surfaces. A transthoracic echocardiogram revealed severe abnormalities of left-ventricular-wall motion and function, in contrast to a normal study ve months before admission. A radiograph of the chest was normal. A radionuclide ventilationperfusion scan (Fig. 1) showed a low probability of a pulmonary embolus. An ultrasonographic examination of the abdomen showed increased echogenicity that was consistent with a diffuse fatty change in the liver, without focal abnormalities. The gallbladder was contracted, and the common bile duct was not dilated. The portal vein was patent, with normal hepatopetal ow. The kidneys appeared normal, and no ascites was detected. A computed tomographic (CT) scan of the abdomen (Fig. 2) conrmed the fatty change in the liver. A serum screening test for drugs of abuse was negative. A test for hepatitis B surface antibody was positive; tests for hepatitis B surface antigen, antinuclear antibodies, rheumatoid factor, antibody to the human immunodeciency virus (HIV), antineutrophil cytoplasmic antibodies, Bence Jones proTable 3. Arterial-Blood Gas Values on Admission.*
VARIABLE VALUE

Figure 1. Perfusion (Top Panel) and Ventilation (Bottom Panel) Portions of the VentilationPerfusion Scan, Demonstrating a Low Probability of Pulmonary Embolism.

Partial pressure of oxygen (mm Hg) Partial pressure of carbon dioxide (mm Hg) pH

92 25 7.57

*Measurements were performed while the patient was breathing room air.

tein, cryoprotein, and antimitochondrial antibodies were negative. The results of serum immunoelectrophoresis were normal. Verapamil, cimetidine, oxazepam, vitamin K, thiamine, and a multivitamin tablet were administered daily. Six units of packed red cells were transfused during the rst four hospital days, and the hematocrit rose to 35.5 percent. Repeated stool tests for occult blood gradually became negative. The temperature was normal on most occasions and never exceeded 37.5C. The cutaneous lesions began to resolve slowly after the ninth hospital day. The patients appetite gradually returned, and he began to eat normally. A urine culture yielded an abundant growth of Escherichia coli, and ciprooxacin was added to the medications; a blood culture was sterile. A biopsy of the cutaneous lesions revealed a focal inammatory inltrate, with scattered hemosiderin-laden macrophages and marked papillary dermal mucinosis; no evidence of a malignant tumor was detected. A biopsy of the gingival lesion showed supercial ulceration with subjacent granulation tissue. A biopsy of the bone marrow showed no denite abnormality; there were adequate megakaryocytes and iron stores. Re-

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

Vol. 333

No. 25

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

1697

Figure 2. Abdominal CT Scan, Obtained without the Intravenous Administration of Contrast Material, Showing Marked Fatty Inltration of the Liver.

peated electrocardiograms revealed more extensive inversion of T waves, although the patient reported no chest pain and the creatine kinase levels were not elevated. A dipyridamolethallium scan showed no evidence of ischemia or a myocardial scar. An echocardiogram showed substantial improvement in the left ventricular abnormalities. The patient was discharged in improved condition on the 20th hospital day. Diagnostic information was received. DIFFERENTIAL DIAGNOSIS DR. JAMES L. MEISEL*: I cared for this patient and was asked to review our approach to the diagnosis. At the time of admission a systemic vasculitis, either directly or indirectly related to hepatitis B or another infection or a malignant tumor, was considered the most likely diagnosis. The patient was admitted for packedcell transfusion and further evaluation. May we review the radiologic ndings? DR. RHONDA K. MCDOWELL: A chest lm obtained on admission was normal. The equilibrium phase of the ventilation portion of the ventilationperfusion examination (Fig. 1) demonstrates complete ventilation of both lungs. The perfusion portion of the examination reveals peripheral abnormalities in a nonsegmental distribution. The ndings indicate a low probability of a pulmonary embolus. The abdominal ultrasonographic study reveals a marked increase in hepatic echogenicity. A single slice from the CT examination (Fig. 2), which was performed without the administration of contrast material, shows a severe fatty change of the liver, manifested by intravascular blood with a much higher density than that of the parenchyma.
*Assistant in medicine, General Internal Medicine Unit, Massachusetts General Hospital; instructor in medicine, Harvard Medical School.

DR. MEISEL: There was no obvious source of systemic infection. This conclusion is supported by the normal temperature and leukocyte count, the negative routine blood cultures, the negative test for antibodies to HIV, and the clinical improvement without specic therapy. Acute hepatobiliary disease seemed unlikely, since neither the alanine aminotransferase level nor the alkaline phosphatase level was markedly elevated and the ultrasonographic study of the abdomen did not provide contributory evidence. The ndings from the cutaneous and gingival biopsies were not consistent with vasculitis or a malignant disorder, such as leukemia or Kaposis sarcoma. The patients stable weight and normal chest lm, the ndings on the abdominal CT scan, and the results of the bone marrow studies made widespread neoplasia unlikely. The striking electrocardiographic and echocardiographic abnormalities were thought to be due to ischemia in the setting of severe anemia. The diagnosis of ischemia was not substantiated, however, by the occurrence of chest pain, serial creatine kinase measurements, or a thallium study. Although only supportive therapy was offered, all the abnormalities improved over the patients 20-day hospital stay. Since this man clearly had an underlying disorder when he presented, I revisited the differential diagnosis of two of the most specic features of the case: anemia and skin lesions. The anemia was thoroughly evaluated. The macrocytosis was attributed to alcohol abuse, since the condition was chronic and associated with normal vitamin B12 and folate levels and a normal bone marrow study, which showed normal erythrocyte production. Examination of the peripheral-blood smear did not show evidence of hemolysis, despite the elevations in the unconjugated bilirubin and lactate dehydrogenase levels. Since red cells were being produced and were not being destroyed peripherally, they must have been lost somewhere. Although the stool test was positive for occult blood on admission, chronic blood loss was ruled out by the demonstration of adequate iron stores in the bone marrow. The patient reported no trauma, and there was no evidence of acute intrathoracic, gastrointestinal, or retroperitoneal bleeding. The purpura, however, offered ample evidence of recent cutaneous and presumably intramuscular hemorrhage. The hyperbilirubinemia was due to resorption of the extravasated blood. Although several dermatologic diseases can produce purpura, the clinical features in this case were those of a systemic disease, such as vasculitis, infectious or noninfectious emboli, clotting disorders, syndromes possibly associated with immune-complex deposition, and congenital and acquired vascular abnormalities.1 Most of this patients lesions were not the raised subcutaneous hemorrhages usually described as palpable purpura, which are typical of vasculitis or infectious emboli. Cutaneous vasculitis can be divided into two types: microscopical polyangiitis and polyarteritis nodosa. HenochSchnlein purpura, an example of the former type, usually occurs in young persons, with symptoms

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

1698

THE NEW ENGLAND JOURNAL OF MEDICINE

Dec. 21, 1995

of allergy, such as pruritus or erythema, and rarely results in a blood loss sufcient to cause anemia.2 Another example is Goodpastures syndrome, which was excluded as a diagnosis in this case because of the absence of pulmonary and renal involvement and the negative test for antineutrophil cytoplasmic antibodies. Polyarteritis nodosa is a multisystem disease that may involve medium-sized as well as small blood vessels. It can be associated with hepatitis B infection3 and may present with weakness, anorexia, and myocardial infarction due to coronary arteritis. Although purpura may occur, painful subcutaneous nodules and ulcers are characteristic.4 Characteristic features of vasculitis were not evident in the skin-biopsy specimen from this patient. Infectious emboli may cause purpura because of cutaneous infarction. Meningococcemia, disseminated gonococcal infection, and Rocky Mountain spotted fever are unlikely without a prodromal fever, meningismus, arthralgias, or lesions on the palms or soles; in addition, the patients condition improved without specic therapy. Ecthyma gangrenosum is associated with infection by gram-negative rods, such as the E. coli found in this patients urine. The lesions, however, are usually vesicular, with erythema surrounding a central area of necrosis, and histologic examination shows bacterial invasion of blood vessels. We can safely assume that this disease was not tuberculosis, in view of the absence of a cough or history of exposure, the normal lm of the chest, and the spontaneous clinical recovery. Malaria may present with nonspecic symptoms, extreme weakness, and a normochromic and normocytic anemia. Cutaneous hemorrhage, however, is usually seen in association with disseminated intravascular coagulation or other severe manifestations, which this patient did not have. The distribution and extent of the lesions were not consistent with cholesterol embolism or with emboli from an intracardiac source for example, an atrial myxoma or nonbacterial thrombotic endocarditis. The latter diagnosis also was not supported by the echocardiographic ndings and would probably have involved the central nervous system as well. Although fat embolism after a major injury to bone or soft tissue can result in petechiae, this patient had not undergone such trauma. Abnormalities of hemostasis and coagulation can result in petechiae and purpura. The normal platelet count ruled out quantitative hemostatic disorders, such as idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura. The bleeding time was not determined, however, to rule out a problem with platelet function. A congenital abnormality was improbable, since there was no history of bleeding. Myeloproliferative disease, dysproteinemia, and uremia were ruled out as causes of acquired platelet dysfunction, and liver disease was unlikely. It is difcult to exclude the possibility of a drug-induced disorder, since many foods and drugs, including alcohol and the nearly ubiquitous aspirin, adversely affect platelet function.5 Nevertheless, the onset of this patients symptoms, including

the profound fatigue and possible cardiac involvement, made that diagnosis improbable. Normal prothrombin and partial-thromboplastin times can be considered to rule out, with very rare exceptions,6 an acquired coagulopathy. Cryoglobulinemia was an interesting consideration. Small-vessel thromboses may occur, and purpura is a common nding.7 The disease is usually seen in the setting of an immunoproliferative or autoimmune disorder but has also been associated with both hepatitis B and hepatitis C.8 In this case, however, cryoprotein was not found in the blood or precipitated within the dermal vessels in the skin-biopsy specimen. Patients with Waldenstrms macroglobulinemia may have bleeding complications related to immune-complex deposition. The normal results of serum immunoelectrophoresis ruled out this condition and other so-called hyperglobulinemic purpuras.9 Autoerythrocyte sensitization is an unusual disorder in which spontaneous, painful ecchymoses develop, accompanied by headaches and nausea. The pathogenesis is unclear. Although laboratory studies have suggested that the problem lies in the autosensitization of a component of the red-cell membrane,10 purpura most often appears during periods of extreme emotional stress in patients with certain personality types.11 The syndrome occurs almost exclusively in middle-aged women. Vascular abnormalities, both inherited and acquired, constitute the nal group of causes of purpura. In such cases the tourniquet test indicates capillary fragility (the RumpelLeede phenomenon). Many of the diseases already discussed, including vasculitis, paraproteinemias, and purpura due to infections, also cause bleeding as a result of damage to blood vessels. Congenital vascular malformations can produce bleeding disorders. Both the patients age at the onset of his illness and its clinical manifestations rule out connective-tissue disorders such as the EhlersDanlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. Furthermore, this mans subcutaneous hemorrhages were not the blanchable, permanent, minute lesions seen in patients with hereditary hemorrhagic telangiectasia. The intake of various foods and medications has been associated with the idiosyncratic development of vascular purpura. Generally, however, it is of little clinical importance.2 Amyloidosis is an acquired cause of vascular fragility. Amyloid is an insoluble brillar protein. There are at least ve types of amyloidosis: primary, secondary, hereditary systemic, local, and senile. The secondary structure of the protein involved determines the pathophysiologic pattern and clinical presentation of each type.12 In primary amyloidosis the brils consist of immunoglobulin light-chain fragments called amyloid light chains, which are also found in amyloidosis associated with multiple myeloma and Waldenstrms macroglobulinemia. Deposits accumulate in the skeletal muscle, heart, skin, tongue, gastrointestinal tract, peripheral nerves, liver, spleen, and kidneys.13 Inltration of cuta-

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

Vol. 333

No. 25

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

1699

neous vessels may produce ecchymoses, particularly on the upper part of the body,14 gastrointestinal hemorrhage may occur, and local involvement of the biliary tree may cause cholestasis in rare cases.15 A deciency of factor X associated with amyloidosis can present with purpura and a severe microangiopathic hemolytic anemia.16 Secondary amyloidosis is associated with chronic infection or inammation. The brillar protein that accumulates is amyloid A, which is probably a derivative of the normal acute-phase reactant known as serum amyloid A.17 In secondary amyloidosis amyloid A may be deposited in the liver, spleen, adrenal glands, and kidneys. This disorder most often presents with the nephrotic syndrome. The heart is primarily affected in senile amyloidosis, and electrocardiographic abnormalities are common.12 A potentially fatal sensitivity to digitalis may develop. The diagnosis of amyloidosis is made on the basis of a biopsy of an involved organ. If the organ is inaccessible or the risk of hemorrhage is too high, a rectal, gingival, skin,14 bone marrow, or subcutaneous-fat biopsy may yield the correct diagnosis.12 The microscopical nding of green birefringence with polarized light after staining with Congo red is diagnostic. Amyloid lightchain and amyloid A proteins can be differentiated by treatment with potassium permanganate. In this case the ndings in the biopsy specimens were not consistent with amyloidosis. Moreover, if this disorder had caused the patients symptoms, they would not have resolved spontaneously. A textbook of medicine published in 1920 aptly describes the diagnosis in this case: A disorder of metabolism of unknown origin, characterized by great debility, with anaemia, a spongy condition of the gums, and a tendency to haemorrhages. . . . The juice of two or three lemons or oranges daily and a diet of plenty of meat and fresh vegetables sufce to cure all cases . . . unless far advanced.18 A fatal disease of 18thcentury British mariners,19 scurvy is another important cause of acquired vascular fragility. Vitamin C was isolated in 1928,20 and by the time of World War II sufcient knowledge had accumulated to change markedly the epidemiologic pattern of the disease caused by a deciency of vitamin C. Today, adult scurvy is most prevalent among indigent elderly persons living in urban areas, particularly among edentulous men who live alone and prepare their own food.21,22 Alcoholism, esophageal reux,22,23 and fad dieting24 are additional risk factors. Vitamin C, or ascorbic acid, is a necessary cofactor in the synthesis of collagen.25 A deciency of vitamin C results in the breakdown of connective tissue in and around the walls of blood vessels. The disease is thus characterized by bleeding due to capillary fragility, poor healing of wounds, and, in children, bone abnormalities. The most characteristic physical nding is the perifollicular hemorrhage, a hyperkeratotic follicle surrounded by a pink halo. Hairs may acquire a corkscrew appearance. Other manifestations include purpura, par-

ticularly in a saddle-shaped distribution on the buttocks and thighs, which may coalesce; intramuscular hemorrhage; gingival involvement in dentulous patients; edema; exertional dyspnea26; and emotional changes, including apathy.27 Anemia is common and multifactorial. The causes include hemorrhage into tissues, altered metabolism and deciencies of folate and iron, gastrointestinal blood loss, and intravascular hemolysis.22 Icterus and fever are late signs. Death may occur suddenly. Other, less common manifestations of scurvy include ocular hemorrhages,28 Sjgrens (sicca) syndrome,29 femoral neuropathy resulting from hemorrhage into the femoral sheaths,30 impaired vascular reactivity,31 and arthritis.26 Specic descriptions of cardiac involvement in patients with scurvy are limited. Shafar32 reported two cases in which ST-segment and T-wave electrocardiographic changes resolved with the repletion of ascorbic acid. Sament33 described many cases of sudden death and of reversible electrocardiographic abnormalities in patients in Africa. A case of cardiomegaly and generalized edema without electrocardiographic changes was reported by Singh and Chan.34 With regard to the metabolism of ascorbic acid, urinary retention of ingested radiolabeled ascorbic acid begins when the bodys total pool of ascorbic acid falls below 1500 mg; maintenance of that level requires an intake of approximately 60 mg of ascorbic acid daily. The symptoms of scurvy appear when the pool drops below 300 mg. A daily dose of 10 mg of ascorbic acid will treat and prevent scurvy but will not substantially increase the pool above 300 mg, leaving little margin for deprivation. Since vitamin C catabolism occurs at a rate of 2.2 to 4.1 percent per day in patients with scurvy, it is estimated that a daily dose of 60 mg, the recommended dietary allowance in the United States, would offer protection against scurvy for at least one month if the intake of ascorbic acid were to cease.25 Studies of nutritional status with respect to ascorbic acid include measurements of urinary ascorbic acid levels with vitamin C loading and measurements of leukocyte and serum ascorbic acid levels. Since the leukocyte level provides information about body stores, it is the preferred objective diagnostic test for scurvy.35 The diagnostic information received in the case under discussion was the patients dietary history. When asked about his diet, he described a daily intake that consisted exclusively of one or two commercially prepared pastries, a can of spaghetti and meatballs, and six to eight beers. His diet thus contained little or no ascorbic acid, accounting for essentially all the manifestations of his illness and for its striking response to a well-balanced diet and daily multivitamins while he was hospitalized. The ascorbic acid content of the hospital diet varied with his menu selection; the vitamin supplement contained 60 mg of ascorbic acid, a dose more than adequate for the treatment of scurvy. Intramyocardial hemorrhage may have been responsible for the transient abnormalities of left-ventricular-

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

1700

THE NEW ENGLAND JOURNAL OF MEDICINE

Dec. 21, 1995

wall motion and function, which occurred without evidence of infarction or vasculitis. CLINICAL DIAGNOSES Purpura of unknown cause. Cardiomyopathy. ? Scurvy. DR. JAMES L. MEISELS DIAGNOSIS Scurvy. PATHOLOGICAL DISCUSSION DR. EUGENE J. MARK: We reviewed the slides of the gingival- and skin-biopsy specimens to corroborate the clinical diagnosis. There was extensive hemorrhage in the tissue below as well as distant from the gingival ulcer, a nding consistent with the capillary fragility of scurvy. The hemorrhage in scurvy is due to an impairment in the hydroxylation of procollagen, which leads to instability of the blood-vessel walls. Ultrastructural examination in scorbutic guinea pigs reveals depletion of pericapillary collagen, loss of the capillary basement membrane, disruption of the cytoplasm of endothelial cells, and separation of endothelial-cell junctions.36 In retrospect, the skin-biopsy specimens showed a slight perivascular lymphohistiocytic inltrate in the papillary dermis and around a curved hair follicle (Fig. 3). The infundibulum of the follicle was distended by keratin (Fig. 4). The papillary dermis contained mucinous material, which was stained by the colloidal-iron method (Fig. 5). Fresh hemorrhage was present in the supercial papillary dermis (Fig. 6). The perifollicular inammation, follicular keratosis, and hemorrhage are consistent with scurvy 37-39 and other nutritional deciencies. The presence of a hair in the stratum corneum cut at multiple levels (Fig. 5) reects the corkscrewshaped hair that is characteristic of scurvy. Most animals can synthesize vitamin C from glucose. Humans, other primates, and guinea pigs in the laboratory are the principal victims of scurvy. Both infants and elderly persons may die suddenly from the disease. Right ventricular hypertrophy is found in infants.40 Specic cardiac lesions have not been described in adults, but hemorrhage in the myocardium has been observed in guinea pigs,36 and cardiac hemorrhage may have been the cause of the evanescent electrocardiographic changes in this patient. Another cause of death is fulminant bacterial or tuberculous infection, which is probably related to defective wound healing and an inability to wall off the infection. DR. MEISEL: The plasma and leukocyte ascorbic acid levels were normal after 20 days repletion of ascorbic acid. A colonoscopic study, performed to evaluate the patients previously guaiac-positive stool specimens, was normal. The electrocardiographic ndings reverted to the pattern of those reported before his admission to the hospital. The 24-hour urinary free cortisol level and thyroid function, determined soon after discharge, were also normal, indicating that Cushings

Figure 3. Biopsy Specimen of the Skin with Curved Hair Follicle (Top), Orthokeratotic Scale (Right), and Slight, Supercial, Perivascular Monocytic Inltration (Hematoxylin and Eosin, 60).

syndrome and myxedema, respectively, did not cause the purpura due to vascular fragility. On a diet replete with fruit, the patient has regained his appetite, no longer reports malaise, and has continued to feel well overall. DR. ROBERT B. COLVIN: Could vitamin B1 deciency also have contributed to the patients cardiac problem?

Figure 4. Dilated Infundibulum of a Hair Follicle with a Keratotic Plug (Hematoxylin and Eosin, 180).

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

Vol. 333

No. 25

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

1701

begins.43 Dropsy presumably referred to beriberi. The case of an alcoholic patient with scurvy and the WernickeKorsakoff syndrome due to deciencies of ascorbic acid and thiamine, respectively, was discussed at one of these exercises nine years ago.44 That patient, however, did not have dropsy. DR. MEISEL: Multiple vitamin deciencies are obviously much more common in patients with scurvy than in animals with the experimentally induced disease. Before the 1970s several experiments were performed with ascorbic acid deprivation exclusively, and much of our clinical information comes from the data derived from these studies.26 ANATOMICAL DIAGNOSIS Scurvy. REFERENCES
1. Bolognia J, Braverman IM. Skin manifestations of internal disease. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, eds. Harrisons principles of internal medicine. 13th ed. New York: McGraw-Hill, 1994:290-307. 2. Bithell TC. Bleeding disorders caused by vascular abnormalities. In: Lee GR, Bithell TC, Foerster J, Athen JW, Lukens JN. Wintrobes clinical hematology. 9th ed. Vol. 2. Philadelphia: Lea & Febiger, 1993:1374-89. 3. Sergent JS, Lockshin MD, Christian CL, Gocke DJ. Vasculitis with hepatitis B antigenemia: long-term observation in nine patients. Medicine (Baltimore) 1976;55:1-18. 4. Gravallese EM. Systemic vasculitis. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in general medicine. 4th ed. Vol. 2. New York: McGraw-Hill, 1993:2167-78. 5. Schrier SL. Disorders of hemostasis and coagulation. In: Rubenstein E, Federman DD, eds. Scientic American medicine. New York: Scientic American, 1993:331-2. 6. Handin RI. Bleeding and thrombosis. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, eds. Harrisons principles of internal medicine. 13th ed. New York: McGraw-Hill, 1994:317-22. 7. Brouet JC, Clouvel JP, Danon F, Klein M, Seligmann M. Biologic and clinical signicance of cryoglobulins: a report of 86 cases. Am J Med 1974;57: 775-88. 8. Bloch KJ. Cryoglobulinemia and hepatitis C virus. N Engl J Med 1992;327: 1521-2. 9. Strauss WG. Purpura hyperglobulinemia of Waldenstrm: report of a case and review of the literature. N Engl J Med 1959;260:857-60. 10. Kremer WB, Mengel CE, Nowlin JB, Nagaya H. Recurrent ecchymoses and cutaneous hyperreactivity to hemoglobin: a form of autoerythrocyte sensitization. Blood 1967;30:62-73. 11. McDufe FC, McGuire FL. Clinical and psychological patterns in autoerythrocyte sensitivity. Ann Intern Med 1965;63:255-65. 12. Glenner GG. Amyloid deposits and amyloidosis: the b -brilloses. N Engl J Med 1980;302:1283-92, 1333-43. 13. Kyle RA, Greipp PR. Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983;58:665-83. 14. Rubinow A, Cohen AS. Skin involvement in generalized amyloidosis: a study of clinically involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. Ann Intern Med 1978;88:781-5. 15. Rubinow A, Koff RS, Cohen AS. Severe intrahepatic cholestasis in primary amyloidosis: a report of four cases and a review of the literature. Am J Med 1978;64:937-46. 16. Jacobson RJ, Sandler SG, Rath CE. Systemic amyloidosis associated with micro-angiopathic haemolytic anaemia and factor X (Stuart factor) deciency. S Afr Med J 1972;46:1634-7. 17. Franklin EC. Immunopathology of the amyloid diseases. Hosp Pract (Off Ed) 1980;15(9):70-7. 18. Osler W, McCrae T. The principles and practice of medicine. New York: Appleton, 1920. 19. Stewart CP, Guthrie D, eds. Linds treatise on scurvy: a bicentenary volume containing a reprint of the rst edition of A treatise on the scurvy. Edinburgh, Scotland: University Press, 1953. 20. Lee RV. Scurvy: a contemporary historical perspective. Conn Med 1983; 47:629-32, 703-4; 1984;48:33-5. 21. Wilson JD. Vitamin deciency and excess. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, eds. Harrisons principles of internal medicine. 13th ed. New York: McGraw-Hill, 1994:472-80.

Figure 5. Dermal Mucinosis (Blue) and Hair Follicle Cut at Several Levels in the Epidermis (Arrows) (Colloidal Iron, 180).

DR. MEISEL: Low cardiac output due to beriberi should be considered in any alcoholic patient who presents with heart failure, particularly if metabolic acidosis is present. Jugular venous distention, cardiomegaly, shock, or a hyperdynamic state is usually evident, however, in high-output heart failure.41,42 WernickeKorsakoff neurologic ndings would have made thiamine deciency a more likely factor in this patient. DR. MARK: Sydenham is said to have written in the 17th century, Where the scurvy ends, then the dropsy

Figure 6. Erythrocytes in the Supercial Dermis (Hematoxylin and Eosin, 350).

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.

1702

THE NEW ENGLAND JOURNAL OF MEDICINE

Dec. 21, 1995

22. Reuler JB, Broudy VC, Cooney TG. Adult scurvy. JAMA 1985;253:8057. 23. Leung FW, Guze PA. Adult scurvy. Ann Emerg Med 1981;10:652-5. 24. Sherlock P, Rothschild EO. Scurvy produced by a Zen macrobiotic diet. JAMA 1967;199:794-8. 25. Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 1986;314:892-902. 26. Hodges RE, Hood J, Canham JE, Sauberlich HE, Baker EM. Clinical manifestations of ascorbic acid deciency in man. Am J Clin Nutr 1971;24:43243. 27. Kinsman RA, Hood J. Some behavioral effects of ascorbic acid deciency. Am J Clin Nutr 1971;24:455-64. 28. Hood J, Hodges RE. Ocular lesions in scurvy. Am J Clin Nutr 1969;22:55967. 29. Hood J, Burns CA, Hodges RE. Sjgrens syndrome in scurvy. N Engl J Med 1970;282:1120-4. 30. Hood J. Femoral neuropathy in scurvy. N Engl J Med 1969;281:1292-3. 31. Abboud FM, Hood J, Hodges RE, Mayer HE. Autonomic reexes and vascular reactivity in experimental scurvy in man. J Clin Invest 1970;49:298307. 32. Shafar J. Rapid reversion of electrocardiographic abnormalities after treatment in two cases of scurvy. Lancet 1967;2:176-8.

33. Sament S. Cardiac disorders in scurvy. N Engl J Med 1970;282:282-3. 34. Singh D, Chan W. Cardiomegaly and generalized oedema due to vitamin C deciency. Singapore Med J 1974;15:60-3. 35. Sauberlich HE. Vitamin C status: methods and ndings. Ann N Y Acad Sci 1975;258:438-49. 36. Gore I, Wada M, Goodman ML. Capillary hemorrhage in ascorbic-aciddecient guinea pigs: ultrastructural basis. Arch Pathol 1968;85:493-502. 37. Walker A. Chronic scurvy. Br J Dermatol 1968;80:625-30. 38. Ellis CN, Vanderveen EE, Rasmussen JE. Scurvy: a case caused by peculiar dietary habits. Arch Dermatol 1984;120:1212-4. 39. Ackerman AB. Histologic diagnosis of inammatory skin diseases: a method by pattern analysis. Philadelphia: Lea & Febiger, 1978. 40. Follis RH Jr. Sudden death in infants with scurvy. J Pediatr 1942;20:347-51. 41. Naidoo DP. Beriberi heart disease in Durban: a retrospective study. S Afr Med J 1987;72:241-4. 42. Fowler NO. High-cardiac-output states. In: Schlant RC, Alexander RW, eds. Hursts the heart: arteries and veins. 8th ed. Vol. 1. New York: McGrawHill, 1994:503-13. 43. Watt J. Nutrition in adverse environments. 1. Forgotten lessons of maritime nutrition. Hum Nutr Appl Nutr 1982;36:35-45. 44. Case Records of the Massachusetts General Hospital (Case 33-1986). N Engl J Med 1986;315:503-8.

The Massachusetts General Hospital wishes to acknowledge the generous support of Glaxo, Inc., whose sponsorship makes possible the continued preparation of the Case Records.

35-MILLIMETER SLIDES FOR THE CASE RECORDS

Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, of the pertinent x-ray lms, electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a standard 35-mm projector. These slides, which illustrate the current cases in the Journal, are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately 250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114 (Telephone [617] 726-4369).

The New England Journal of Medicine Downloaded from nejm.org on November 13, 2012. For personal use only. No other uses without permission. Copyright 1995 Massachusetts Medical Society. All rights reserved.