Case Report Pulmonary Hypertension and Familial Mediterranean Fever: A Previously Unrecognized Association
WILLIAM J. JOHNSON, M.D., Division ofNephrology and Internal Medicine; J. T. LIE, M.D., Section ofMedical Pathology
Familial Mediterranean fever is an autosomal recessive inherited disorder characterized by recurrent episodes of fever accompanied by inflammation of the peritoneum, pleura, synovial membranes, and skin. The disorder predominantly affects persons of Mediterranean origin. The most serious complication of the disease is amyloidosis, which is the cause of death in a substantial proportion of adult patients with the disorder. Only one previous report hits described pulmonary hypertension in a patient with systemic amyloidosis associated with multiple myeloma. Herein we describe the first known occurrence of pulmonary hypertension due to pulmonary amyloidosis in a 48-year-old woman with familial Mediterranean fever. Postmortem examination showed extensive deposits of amyloid in the pulmonary vessels, alveolar capillary walls, and myocardium, which explained the hypoxia, hypotension, and terminal cardiac arrhythmias that were the immediate cause of death in this patient.
Familial Mediterranean fever (also known as familial recurrent polyserositis) is an autosomal recessive inherited disorder that is characterized by recurrent episodes of fever and inflammation that mainly involves the peritoneum, pleura, synovial membranes, and skin. 1 It occurs predominantly in persons living in or originating from the Mediterranean shores, especially those of Jewish (Sephardic more commonly than Ashkenazic ancestry), Arabian, Turkish, and Armenian descent. The disease is seldom encountered outside the Mediterranean countries except among the emigrants or travelers from that region.' Because of its protean clinical manifestations, the diagnosis of familial Mediterranean fever can be challenging, and it often necessitates a high degree of clinical acuity. A substantial proportion of adult patients who have the disease die of amyloidosis.' Only one previously published report has described pulmonary hypertension in a patient with systemic amyloidosis associated with multiple myeloma." Herein we describe the first known occurrence of pulmonary hypertension due to pulmonary amyloidosis in a patient with familial Mediterranean fever. Address reprint requests to Dr. W. J. Johnson, Division of Nephrology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:919-925, 1991
REPORT OF CASE A 48-year-old woman of Eastern Mediterranean origin came to our institution for consideration for renal transplantation because of chronic renal failure. Thrombocytopenia had also been diagnosed. Background.-When the patient was I year of age, renal colic developed. On roentgenologic examination, three radiopaque stones were found, two of which were passed spontaneously. When she was 10 years of age, recurrent febrile episodes developed with temperatures as high as 41°C. These occurrences were characterized by a sudden onset of fever followed by chills and profuse sweating; they subsided spontaneously within a few days after onset. During this period, routine urinalyses first showed microscopic hematuria and pyuria without substantial proteinuria; in addition, pain, redness, and swelling of the ankles persisted for weeks. The arthralgia was not closely associated with the febrile episodes. The patient underwent a tonsillectomy and adenoidectomy at 12 years of age and a nephrolithotomy on the right side at 13 years of age. No improvement was noted after either procedure. The only other finding at surgical exploration was hydronephrosis. The abnormal findings on urinalyses, the febrile episodes, and the arthropathy persisted without evidence of azotemia. During a routine physical examination at 31 years of age, she was found to have 919
920
FAMILIAL MEDITERRANEAN FEVER
hepatosplenomegaly. A lymph node biopsy specimen showed only nonspecific.reticular hyperplasia, and results of a bone marrow examination were normal. Because the patient was thought to have familial Mediterranean fever, at 40 years of age she received colchicine (in a daily dose of 2 mg orally) for 8 months. During this period, the febrile episodes ceased permanently, and the arthropathy was alleviated; however, the ingestion of colchicine resulted in gastrointestinal side effects and alopecia. Therefore, colchicine therapy was discontinued because of the initial presence of azotemia, which progressed for several months to oliguric renal failure. In 1981, the patient (who was 40 years old) experienced a single uremic seizure, and continuous ambulatory peritoneal dialysis was initiated. Three months later, the dialysis treatment was changed to twice weekly intermittent hemodialysis because of technical problems with the peritoneal catheter. After the frequency of dialysis was increased to three times weekly, the pericarditis and pericardial effusion diminished. Epistaxis, bleeding of the gums, and melena developed in 1983, for which the patient needed as many as three blood transfusions per week. For the first time, thrombocytopenia and leukopenia were noted. In 1985, esophagogastroscopy revealed capillary bleeding in the distal esophagus. Gastrointestinal bleeding continued despite laser sclerotherapy; it stopped only after administration of heparin during dialysis was discontinued. A computed tomographic scan of the abdomen disclosed an enlarged spleen that contained several cystic lesions, one of which was calcified. During 1988 and 1989, the patient underwent examinations at two organ transplantation centers in the United States. Transplantation was not recommended because of multiple organ involvement and severe thrombocytopenia. A heparin-independent antiplatelet antibody was identified. Examinations confirmed the presence of hepatosplenomegaly and also raised the possibility of pulmonary hypertension. Echocardiography revealed biventricular hypertrophy without severe valvular disease and a high ejection fraction. Bone marrow examination and analysis of fat aspirate failed to disclose evidence of amyloidosis. Results of serologic tests for schistosomiasis and cryptococcosis were negative. The family history was important in that both parents had died at an advanced age: one had parkinsonism, and the other had hypertension and diabetes. Two aunts had fevers in conjunction with pain in joints. A sister had died in the third decade of life of renal failure attributed to nephrolithiasis and chronic pyelonephritis. Two other sisters had fevers but recovered. The patient herself had experienced two spontaneous abortions and two normal pregnancies. A daughter had recurrent episodes of monarthritis that involved only the ankles without febrile episodes. None of the
Mayo Clin Proc, September 1991, Vol 66
family members had had a definite diagnosis of familial Mediterranean fever. Course of Disease.-During the last year of life, the patient experienced gradual weight loss (14 kg), onset of a chronic nonproductive cough, exertional dyspnea, and postural hypotension. Although previously active and energetic, she became increasingly debilitated, hypoxic, and dependent on oxygen therapy. Palpitation occasionally occurred that was characterized by multiple atrial premature beats and first-degree atrial block with junctional escape. Shortly after the initial examination at our institution, the patient was hospitalized because of lethargy, dizziness, weakness, and shortness of breath after dialysis treatment. A chest roentgenogram showed cardiomegaly, a prominent pulmonary artery, a diffuse interstitial process throughout the lungs, and thickened pleura. Pulmonary function tests revealed low lung volumes (total lung volume was 3.36 liters and vital capacity was 2.31 liters; both values were 71 % of predicted values) and a severely reduced carbon monoxide diffusing capacity (32% of the predicted value). Results were negative on the radionuclide lung scan for metastatic calcification, the ventilation-perfusion scans for pulmonary emboli, and the plethysmograph of the legs for deep vein thrombosis. A computed tomographic scan of the chest demonstrated mediastinal adenopathy, a diffuse interstitial process that involved both lungs, and thickening ofthe interalveolar septa.· In addition, innumerable minute nodular changes were noted within the secondary pulmonary lobules. These changes were interpreted as being consistent with pulmonary hypertension. An echocardiogram revealed a moderate increase in left ventricular wall thickness, hyperdynamic systolic function, and an ejection fraction of 78% with obliteration of the apical cavity during systole. The aortic valve showed sclerosis but no stenosis or regurgitation. The mitral valve was mildly thickened, and mild regurgitation was present. The tricuspid valve was mildly thickened, and regurgitation was recorded at 2.8 mls. On peripheral venous injection of indocyanine green dye, the right atrium became densely opacified; a right-to-left shunt was not noted. The cardiac catheterization data are summarized in Table 1. The important findings of these tests were a pronounced increase in right ventricular pressure, severe pulmonary hypertension, and a mild increase in left ventricular end-diastolic pressure. The complete blood cell count revealed pancytopenia and a platelet count of 30,OOO/mm 3• The bone marrow was mildly hyperplastic and had increased megakaryocytes but no amyloidosis. y-Globulin was administered to determine whether the thrombocytopenia was immune-mediated; the platelet count did not increase. A computed tomographic scan of the abdomen disclosed an enlarged spleen with three areas of low density, one of which contained central calcifi-
FAMILIAL MEDITERRANEAN FEVER
Mayo Clio Proc, September 1991, Vol 66
921
Table I.-Hemodynamic Data for a Patient With Pulmonary Hypertension and Familial Mediterranean Fever Pressure (mm Hg) Position of catheter
Systolic
Right atrium Right ventricle Pulmonary artery Pulmonary artery wedge Left ventricle Brachial artery
110 130
Right atrium Right ventricle Pulmonary artery Left ventricle Brachial artery
22 79 90 104 119
Diastolic
Mean
02 saturation (%)
31 94 97
39 29 62 Breathing 100% 02 (masked) 17 12 6-17 37 58 12-23 66 82
Derived values
Breathing room air
Breathing 100% 02 (masked)
Cardiac output (Urnin) Cardiac index (Lrnin/rrr') Total pulmonary resistance (dynes-s-cm") Pulmonary arteriolar resistance (dynes-s-cm")
3.8 2.6 1,816 (normal
WILLIAM J. JOHNSON, M.D., Division ofNephrology and Internal Medicine; J. T. LIE, M.D., Section ofMedical Pathology
Familial Mediterranean fever is an autosomal recessive inherited disorder characterized by recurrent episodes of fever accompanied by inflammation of the peritoneum, pleura, synovial membranes, and skin. The disorder predominantly affects persons of Mediterranean origin. The most serious complication of the disease is amyloidosis, which is the cause of death in a substantial proportion of adult patients with the disorder. Only one previous report hits described pulmonary hypertension in a patient with systemic amyloidosis associated with multiple myeloma. Herein we describe the first known occurrence of pulmonary hypertension due to pulmonary amyloidosis in a 48-year-old woman with familial Mediterranean fever. Postmortem examination showed extensive deposits of amyloid in the pulmonary vessels, alveolar capillary walls, and myocardium, which explained the hypoxia, hypotension, and terminal cardiac arrhythmias that were the immediate cause of death in this patient.
Familial Mediterranean fever (also known as familial recurrent polyserositis) is an autosomal recessive inherited disorder that is characterized by recurrent episodes of fever and inflammation that mainly involves the peritoneum, pleura, synovial membranes, and skin. 1 It occurs predominantly in persons living in or originating from the Mediterranean shores, especially those of Jewish (Sephardic more commonly than Ashkenazic ancestry), Arabian, Turkish, and Armenian descent. The disease is seldom encountered outside the Mediterranean countries except among the emigrants or travelers from that region.' Because of its protean clinical manifestations, the diagnosis of familial Mediterranean fever can be challenging, and it often necessitates a high degree of clinical acuity. A substantial proportion of adult patients who have the disease die of amyloidosis.' Only one previously published report has described pulmonary hypertension in a patient with systemic amyloidosis associated with multiple myeloma." Herein we describe the first known occurrence of pulmonary hypertension due to pulmonary amyloidosis in a patient with familial Mediterranean fever. Address reprint requests to Dr. W. J. Johnson, Division of Nephrology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 66:919-925, 1991
REPORT OF CASE A 48-year-old woman of Eastern Mediterranean origin came to our institution for consideration for renal transplantation because of chronic renal failure. Thrombocytopenia had also been diagnosed. Background.-When the patient was I year of age, renal colic developed. On roentgenologic examination, three radiopaque stones were found, two of which were passed spontaneously. When she was 10 years of age, recurrent febrile episodes developed with temperatures as high as 41°C. These occurrences were characterized by a sudden onset of fever followed by chills and profuse sweating; they subsided spontaneously within a few days after onset. During this period, routine urinalyses first showed microscopic hematuria and pyuria without substantial proteinuria; in addition, pain, redness, and swelling of the ankles persisted for weeks. The arthralgia was not closely associated with the febrile episodes. The patient underwent a tonsillectomy and adenoidectomy at 12 years of age and a nephrolithotomy on the right side at 13 years of age. No improvement was noted after either procedure. The only other finding at surgical exploration was hydronephrosis. The abnormal findings on urinalyses, the febrile episodes, and the arthropathy persisted without evidence of azotemia. During a routine physical examination at 31 years of age, she was found to have 919
920
FAMILIAL MEDITERRANEAN FEVER
hepatosplenomegaly. A lymph node biopsy specimen showed only nonspecific.reticular hyperplasia, and results of a bone marrow examination were normal. Because the patient was thought to have familial Mediterranean fever, at 40 years of age she received colchicine (in a daily dose of 2 mg orally) for 8 months. During this period, the febrile episodes ceased permanently, and the arthropathy was alleviated; however, the ingestion of colchicine resulted in gastrointestinal side effects and alopecia. Therefore, colchicine therapy was discontinued because of the initial presence of azotemia, which progressed for several months to oliguric renal failure. In 1981, the patient (who was 40 years old) experienced a single uremic seizure, and continuous ambulatory peritoneal dialysis was initiated. Three months later, the dialysis treatment was changed to twice weekly intermittent hemodialysis because of technical problems with the peritoneal catheter. After the frequency of dialysis was increased to three times weekly, the pericarditis and pericardial effusion diminished. Epistaxis, bleeding of the gums, and melena developed in 1983, for which the patient needed as many as three blood transfusions per week. For the first time, thrombocytopenia and leukopenia were noted. In 1985, esophagogastroscopy revealed capillary bleeding in the distal esophagus. Gastrointestinal bleeding continued despite laser sclerotherapy; it stopped only after administration of heparin during dialysis was discontinued. A computed tomographic scan of the abdomen disclosed an enlarged spleen that contained several cystic lesions, one of which was calcified. During 1988 and 1989, the patient underwent examinations at two organ transplantation centers in the United States. Transplantation was not recommended because of multiple organ involvement and severe thrombocytopenia. A heparin-independent antiplatelet antibody was identified. Examinations confirmed the presence of hepatosplenomegaly and also raised the possibility of pulmonary hypertension. Echocardiography revealed biventricular hypertrophy without severe valvular disease and a high ejection fraction. Bone marrow examination and analysis of fat aspirate failed to disclose evidence of amyloidosis. Results of serologic tests for schistosomiasis and cryptococcosis were negative. The family history was important in that both parents had died at an advanced age: one had parkinsonism, and the other had hypertension and diabetes. Two aunts had fevers in conjunction with pain in joints. A sister had died in the third decade of life of renal failure attributed to nephrolithiasis and chronic pyelonephritis. Two other sisters had fevers but recovered. The patient herself had experienced two spontaneous abortions and two normal pregnancies. A daughter had recurrent episodes of monarthritis that involved only the ankles without febrile episodes. None of the
Mayo Clin Proc, September 1991, Vol 66
family members had had a definite diagnosis of familial Mediterranean fever. Course of Disease.-During the last year of life, the patient experienced gradual weight loss (14 kg), onset of a chronic nonproductive cough, exertional dyspnea, and postural hypotension. Although previously active and energetic, she became increasingly debilitated, hypoxic, and dependent on oxygen therapy. Palpitation occasionally occurred that was characterized by multiple atrial premature beats and first-degree atrial block with junctional escape. Shortly after the initial examination at our institution, the patient was hospitalized because of lethargy, dizziness, weakness, and shortness of breath after dialysis treatment. A chest roentgenogram showed cardiomegaly, a prominent pulmonary artery, a diffuse interstitial process throughout the lungs, and thickened pleura. Pulmonary function tests revealed low lung volumes (total lung volume was 3.36 liters and vital capacity was 2.31 liters; both values were 71 % of predicted values) and a severely reduced carbon monoxide diffusing capacity (32% of the predicted value). Results were negative on the radionuclide lung scan for metastatic calcification, the ventilation-perfusion scans for pulmonary emboli, and the plethysmograph of the legs for deep vein thrombosis. A computed tomographic scan of the chest demonstrated mediastinal adenopathy, a diffuse interstitial process that involved both lungs, and thickening ofthe interalveolar septa.· In addition, innumerable minute nodular changes were noted within the secondary pulmonary lobules. These changes were interpreted as being consistent with pulmonary hypertension. An echocardiogram revealed a moderate increase in left ventricular wall thickness, hyperdynamic systolic function, and an ejection fraction of 78% with obliteration of the apical cavity during systole. The aortic valve showed sclerosis but no stenosis or regurgitation. The mitral valve was mildly thickened, and mild regurgitation was present. The tricuspid valve was mildly thickened, and regurgitation was recorded at 2.8 mls. On peripheral venous injection of indocyanine green dye, the right atrium became densely opacified; a right-to-left shunt was not noted. The cardiac catheterization data are summarized in Table 1. The important findings of these tests were a pronounced increase in right ventricular pressure, severe pulmonary hypertension, and a mild increase in left ventricular end-diastolic pressure. The complete blood cell count revealed pancytopenia and a platelet count of 30,OOO/mm 3• The bone marrow was mildly hyperplastic and had increased megakaryocytes but no amyloidosis. y-Globulin was administered to determine whether the thrombocytopenia was immune-mediated; the platelet count did not increase. A computed tomographic scan of the abdomen disclosed an enlarged spleen with three areas of low density, one of which contained central calcifi-
FAMILIAL MEDITERRANEAN FEVER
Mayo Clio Proc, September 1991, Vol 66
921
Table I.-Hemodynamic Data for a Patient With Pulmonary Hypertension and Familial Mediterranean Fever Pressure (mm Hg) Position of catheter
Systolic
Right atrium Right ventricle Pulmonary artery Pulmonary artery wedge Left ventricle Brachial artery
110 130
Right atrium Right ventricle Pulmonary artery Left ventricle Brachial artery
22 79 90 104 119
Diastolic
Mean
02 saturation (%)
31 94 97
39 29 62 Breathing 100% 02 (masked) 17 12 6-17 37 58 12-23 66 82
Derived values
Breathing room air
Breathing 100% 02 (masked)
Cardiac output (Urnin) Cardiac index (Lrnin/rrr') Total pulmonary resistance (dynes-s-cm") Pulmonary arteriolar resistance (dynes-s-cm")
3.8 2.6 1,816 (normal
