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Polyglandular endocrine failure in a patient with amyloidosis secondary to familial Mediterranean fever
CLINICAL NEPHROLOGY TEACHING CASE
Polyglandular Endocrine Failure in a Patient With Amyloidosis Secondary to Familial Mediterranean Fever ¨ ztas, MD, Hakan Aksoy, MD, Neval Duman, MD, Bu¨lent Erbay, MD, Kenan Keven, MD, Erkin O and S¸ehsuvar Ertu¨rk, MD ● Familial Mediterranean fever (FMF) is 1 of the major causes of secondary amyloidosis. Renal involvement is the main clinical complication and it mostly presents with nephrotic syndrome and chronic renal failure. Although deposition of amyloid has been reported in several endocrine glands such as the adrenal, thyroid, and testes, clinically significant functional impairment is uncommon. Herein, we describe a patient in whom the diagnosis of FMF was based on molecular screening and who presented with recurrent hypoglycemic attacks and extensive amyloid deposition affecting various organ function including adrenal, thyroid, parathyroid, testes, intestinal system, and the heart. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Hypoglycemia; polyglandular endocrine failure; renal failure; secondary amyloidosis.
A
MYLOIDOSIS IS A systemic disease characterized by extracellular deposition of insoluble fibrillar proteins. Although primary amyloidosis is a plasma cell dyscrasia, secondary amyloidosis is associated with inflammatory or infectious diseases such as familial Mediterranean fever (FMF), tuberculosis, chronic osteomyelitis, and rheumatoid arthritis, in which the extensive deposition of amyloid A protein is distinctive.1,2 Secondary amyloidosis has been reported to involve the kidneys, adrenals, intestine, spleen, liver, and, less commonly, the thyroid, testes, stomach, and the heart. However, the main clinical presentation is renal complication.3,4 Clinically significant amyloid depositions in multiple organs rarely have been reported in secondary amyloidosis. Herein, we describe a patient with secondary amyloidosis who presented with severe hypoglycemic attacks, polyglandular endocrine failure, and severe intestinal involvement. CASE REPORT A 46-year-old man who had end-stage renal disease caused by secondary amyloidosis was admitted to Emergency Service because of acute seizures. He had been on maintenance hemodialysis treatment for 3 years. The history of the patient did not reveal any inflammatory or infectious disease that might lead to secondary amyloidosis. He had a history of chronic diarrhea for 5 years and mild pitting edema on the lower extremities for 2 years. Three years ago, chronic renal failure was diagnosed on a routine investigation before surgery for an inguinal hernia. After the surgery, the patient was referred to the Nephrology Department and he was found to have hypertension, 12 g/day proteinuria, hypoalbuminemia, and an elevated serum creatinine level. Gastroduodenoscopy and colonoscopy had been performed and mul-
tiple biopsies had been taken. There was severe atrophic changes in the intestinal mucosa. Congo red staining had revealed extensive amyloid deposition. Staining by antibody against serum amyloid A protein was positive. Three months later, the patient began chronic hemodialysis treatment 3 times a week. DNA testing was performed for FMF to find out the cause of the secondary amyloidosis. Mixed heterozygote status for M694V/M680I mutations was found at the 10 and 2 exons in the MEFV gene.5 The patient was prescribed colchicine 1 mg/day, however, he was reluctant to take the drug regularly. In recent months, the patient’s appetite decreased and his diarrhea increased. He lost his libido and became impotent. On physical examination, body mass index was 17 kg/m2, blood pressure was 100/60 mm Hg, pulse rate was 112/min, and he had a fever (38.5°C). The patient was unconscious and there were common thin rales and rhonchi in the lungs. Also, there was a diffuse hyperplasia in the thyroid. Laboratory evaluations revealed the following: blood glucose 22 mg/dL, blood urea nitrogen 65 mg/dL, serum creatinine 6.5 mg/dL, albumin 2.1 g/dL, total protein 4.1 g/dL, total cholesterol 34 mg/dL, triglycerides 45 mg/dL, uric acid, 6.2 mg/dL, calcium 7.1 mg/dL, phosphorus 3.1 mg/dL, sodium 137 mEq/L, potassium 3.9 mEq/L, hemoglobin 9 g/dL, leukocytes 7.700/mm3, and erythrocyte sedimentation rate 60 mm/h. The patient was treated with intravenous glucose and subcutaneous glucagon. He regained consciousness and felt better over the following hours, and was admitted to the
From the Departments of Nephrology and Urology, Ankara University Medical School, Ibni Sina Hospital, Ankara, Turkey. Received August 28, 2001; accepted as submitted August 31, 2001. Address reprint requests to Kenan Keven, MD, Yenibati mah. 284. sk, C4/6, Batikent, Ankara, 06370 Turkey. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 1523-6838/01/3806-0052$35.00/0 doi:10.1053/ajkd.2001.29295
American Journal of Kidney Diseases, Vol 38, No 6 (December), 2001: E39
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2
KEVEN ET AL
nephrology department. The other laboratory evaluations were as follows: serum ferritin 321 ng/mL (the patient was on maintenance intravenous iron replacement), folic acid 4.5 ng/dL, vitamin B12 121 pg/mL, serum iron was 58 g/dL, total iron binding capacity was 150 g/dL, liver functions were normal, and viral markers including hepatitis B antigen, hepatitis C antibody, anti-cytomegalovirus (CMV) immunoglobulin (Ig) M, and human immune deficiency virus antibody were negative. Brain computed tomography (CT) showed no abnormality. Chest radiograph revealed pneumonic infiltration on the base of the right lung, and CT showed consolidation and pleural fluid on that side. Parenteral ceftriaxone was started for the lung infection. During the hypoglycemic attack, a blood sample had been taken for hormonal evaluations including insulin, C-peptide, adrenocorticotropic hormone (ACTH), plasma cortisol, thyroid-stimulating hormone (TSH), growth hormone (GH), and prolactin. Insulin level was 6.2 Iu/mL and C-peptide was 1.2 ng/mL. In other recurrent hypoglycemic attacks, similar insulin and C-peptide levels were measured. Because of persistent hypoglycemic attacks, the patient was treated with continuous dextrose infusion along with amino acid and lipid solutions. As shown in Table 1, though there was a response to hypoglycemia in the pituitary gland, no marked adrenal response was revealed. On the other hand, both serum-free T3 and T4 were below the normal range and TSH level was found to be elevated. Parathyroid hormone level was very low (0.85 pg/mL) despite lacking any history of either vitamin D or calcium treatments. Both amylase and lipase levels were within the normal range. Despite high levels of follicle-stimulating hormone (FSH) and leutinizing hormone (LH) levels, total and free testosterone levels were very low, indicating primary testicular pathology. Abdominal ultrasonography and CT, primarily focused on the pancreas and adrenal gland, showed no abnormality except bilaterally decreased renal size. Pituitary magnetic resonance imaging (MRI) showed no abnormality. After these laboratory investigations, ACTH stimulation test was performed with 1 mg depot tetracosactide (Synacten Depot, Ciba Geigy, Basel, Table 1.
Hormonal Status of the Patient on Admission
ACTH pg/mL (5–50) P-cortisol g/dL (6.2–19.4) FSH mIU/mL (1.5–9.7) LH mIU/mL (15–9.3) T. testosterone ng/dL (241–827) F. testosterone pg/mL (8.69–54.69) GH IU/mL (0–26) Sensitive TSH mIU/mL (0.35–5.5) F. T4 pmol/L (10–23) F. T3 pmol/L (2.8–7) Anti Tg IU/mL (0–50) AntiTPO IU/mL (0–15) Prolactin ng/mL (3.7–17.8) Parathormone pg/mL (9–55) Abbreviations: T, total; F, free. *Higher than normal range. †Lower than normal range.
307* 15.11 11.8* 16.5* 10.0† 0.63† 55.4* 18.7* 9.97† ⬍1.54† 2 5.5 100.6* 0.86†
Switzerland), and no significant response was observed. The thyroid was found to be mildly enlarged in ultrasonography and the testes were mildly reduced in size. Fine-needle aspiration biopsy of the thyroid and an open biopsy from the testes showed amyloid deposition. In testes tissue, staining with antibody against serum amyloid A protein was positive. Furthermore, echocardiographic examination was compatible with cardiac amyloidosis, showing restrictive cardiac involvement and typical granular sparkling of left ventricular myocardium. On the basis of the hormonal investigations, polyglandular endocrine involvement causing clinical significant primary hypothyroidism, primary adrenal failure, primary testicular failure, and hypoparathyroidism were diagnosed. After, completion of the hormonal tests, oral prednisolone was started at a dose of 15 mg/day and then dropped to 10 mg/day, oral L-thyroxine 50 g/day and intramuscular 250 mg testosterone propionate every 3 weeks were added subsequently. L-thyroxine was increased to 100 g/day. Parenteral vitamin B12 replacement was started. The patient felt better and the frequency of hypoglycemic attacks decreased. Control chest radiograph at day 15 of antibiotherapy showed resolution of pneumonia. After 3 weeks, the patient still had recurrent hypoglycemia and increased diarrhea. Furthermore, chronic diarrhea, very low lipid levels, and low vitamin B12 level were regarded as malabsorption owing to amyloid deposition, which was shown 3 years ago. For further evaluation of malabsorption, a microscopic examination of stool fat with 36% acetic acid and Sudan III was performed and there were lots of large orange globules representing free fatty acids. A D-xylose test was performed and the blood D-xylose level at the second hour of the test was 0.4 mg/dL, which was very low. Urinary D-xylose extraction could not be measured because of anuria. Total parenteral nutrition was administered for 5 days and prednisolone was given 10 mg/day. Blood glucose levels returned to the normal range, and then intravenous nutrition support was stopped. He was fed orally with glutamineenriched nutrition solution and supported with parenteral lipid and amino acid solutions during each hemodialysis session. Prednisolone dose was continued at 10 mg/day as a maintenance treatment. The patient was discharged and now he is on maintenance hemodialysis treatment without any hypoglycemic attacks.
DISCUSSION
We describe a patient with secondary amyloidosis presenting with severe hypoglycemic attacks. The patient had severe multisystem involvement causing end-stage renal disease, malabsorption, and polyglandular endocrine failure, including primary hypothyroidism, primary adrenal failure, primary testicular failure, and hypoparathyroidism. Cardiac involvement has also indirectly been shown by echocardiography. Despite the lack of any evidence related to FMF in the patient’s history, the patient has been shown to have FMF based on molecular testing.
HYPOGLYCEMIC ATTACKS IN AMYLOIDOSIS
Amyloidosis is a generalized disease and a common finding is renal involvement leading to renal failure and nephrotic syndrome. Less commonly, adrenal, thyroid, intestinal, pituitary, intestinal, and testicular involvements have been reported.6,7 Although, adrenal involvement has been shown to occur in 47% to 96% of patients with amyloidosis, primary adrenal failure caused by amyloidosis rarely has been reported. Arik et al7 reported subclinical adrenocortical failure in 7 of 12 patients with amyloidosis. In our case, the plasma cortisol level was measured under the hypoglycemic condition, which should be accepted as a stimulated level to endogenous increased ACTH level. Although the pituitary gland has adequately responded to hypoglycemia, there was no adrenal response. In addition, an exogenous ACTH stimulation test was performed to assess adrenal function and no marked increase was revealed. On the basis of these findings, subclinical adrenal failure could be overt during the pulmonary infection and both hypoglycemic attacks and hypotension on admission can be explained by adrenal failure. Testicular involvement causing hypogonadism was defined in few cases in the literature.6,8 The mechanism is complete replacement of all testicular structure by amyloid deposition. In our case, because of hypogonadism and a very low testosterone level, testicular amyloid deposition was considered and testes biopsy was performed. Staining of testes tissue with antibody against serum amyloid A protein was found to be positive. To the best of our knowledge, recurrent severe hypoglycemic attacks have not been reported in a patient with amyloidosis. In addition to adrenal failure, intestinal involvement might contribute to hypoglycemia. For the evaluation of absorption function of the intestine, microscopic examination of stool with Sudan III and D-xylose test were performed and severe malabsorption has been observed. The mechanism of the malabsorption is most likely the intestinal amyloid infiltration, which was shown 3 years ago. Therefore, severe malabsorption had an important role, inducing malnutrition in our patient. For the differential diagnosis, colchicine is a drug commonly used in the treatment of FMF, it inhibits epithelial crypt cell division and causes malabsorption, however, the patient was reluctant to take the
3
drug from the beginning of the diagnosis of FMF. Regarding endocrine disease as a cause of hypoglycemia, insulinoma was not likely the reason because both plasma insulin and Cpeptide levels were low during the hypoglycemic attack. Thyroid involvement has been reported to be 43.4% in systemic amyloidosis. Euthyroidism, hypothyroidism, and thyrotoxicosis can be seen in the patients.9,10 In our case, primary hypothyroidism was diagnosed and amyloid involvement was shown by fine-needle aspiration biopsy. In addition, though there was no therapy, which might have a suppressive effect on parathyroid function, the presence of hypoparathyroidism can also be explained by amyloid infiltration of parafollicular cells, however, more definite diagnoses necessitate histopathologic evidence. Although cardiac amyloidosis is a severe problem mainly for primary amyloidosis, it has also been reported in secondary amyloidosis.11,12 The patients might be asymptomatic or they might have symptoms of congestive heart failure. The echocardiography can show diffuse ventricular wall thickening, isolated septal wall thickening, and restrictive pattern of left ventricular diastolic function. Also, characteristic granular sparkling of left ventricular myocardium as seen in our patient is an important finding for cardiac amyloid involvement. In addition to this, our patient had restrictive involvement and mild left ventricular systolic dysfunction, possibly caused by cardiac amyloid deposition. Recently, a gene responsible for FMF was identified on chromosome 16 and the gene product pyrin or marenostrin was reported to be responsible for limiting the intensity of inflammation. The FMF-related mutations change the structure of the protein and impair the function, causing increased onset and persistence of inflammation.5 The cloning of the FMF gene (MEFV) now made it possible to establish a diagnosis of FMF even in patients lacking any evidence of the disease in their history. In literature, the 5 most common missense mutations were defined as M694V, M680I, V726A, and E148Q.13,14 Indeed, though our patient did not have any history related to FMF, he has been found to carry 2 heterozygote mutations for FMF (M694V, M680I). Initial studies have suggested that the presence of the M694V mutation carries a signifi-
4
KEVEN ET AL
cant risk for the development of amyloidosis. However, it has been shown that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient enough to explain the occurrence of amyloidosis in all patients with FMF.13,14 Nevertheless, more studies are needed to clarify the phenotypegenotype relation in patients with FMF amyloidosis. In conclusion, severe hypoglycemic attacks can be a finding of severe diffuse secondary amyloidosis affecting endocrine and intestinal organs. REFERENCES 1. Cohen AS, Connors LH: The pathogenesis and biochemistry of amyloidosis. J Pathol 151:1-10, 1987 2. Kuhlback B, Wegelius O: Secondary amyloidosis. Acta Med Scand 180:737-745, 1966 3. Triger DR, Joekes AN: Renal amyloidosis-a fourteenyear follow-up. QJM 165:15-40, 1973 4. Brandt K, Cathcart ES, Cohen AS: A clinical analyses of the course and prognosis of forty-two patients with amyloidosis. Am J Med 44:955-969, 1968 5. The International FMF Consortium: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797807, 1997 6. Handelsman DJ, Yue DK, Turtle JR: Hypogonadism
and massive testicular infiltration due to amyloidosis. J Urol 129:610-612, 1983 7. Arik N, Tasdemir I, Karaaslan Y, Yasavul U, Turgan C, Caglar S: Subclinical adrenocortical insufficiency in renal amyloidosis. Nephron 56:246-248, 1990 8. Schrepferman CG, Lester DR, Sandlow JI: Testicular amyloid deposition as a cause of secondary azoospermia. Urology 55:145, 2000 9. Erturk S, Duman N, Ates K, Ekinci C, Erbay B, Karatan O, Erdogan G, Ertug E, Dizbay Sak S: Amyloid deposition in the thyroid gland in patients with amyloidosis: An incidence study with fine-needle aspiration biopsy of the thyroid. Nephrol Dial Transplant 10:1473, 1995 10. Duhra P, Cassar J: Thyroid function tests in amyloid goitre. Postgrad Med J 66:304-306, 1990 11. Cacoub P, Axler O, De Zuttere D, Hausfater P, Amoura Z, Walter S, Wechsler B, Godeau P, Piette J: Amyloidosis and cardiac involvement. Ann Med Interne (Paris) 151:611617, 2000 12. Moyssakis I, Triposkiadis F, Rallidis L, Hawkins P, Kyriakidis M, Nihoyannopoulos P: Echocardiographic features of primary, secondary and familial amyloidosis. Eur J Clin Invest 29:484-489, 1999 13. Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E: MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 6:1-6, 1999 14. Tekin M, Yalcinkaya F, Cakar N, Akar N, Misirlioglu M, Tastan H, Tumer N: MEFV mutations in multiplex families with familial Mediterranean fever: Is a particular genotype necessary for amyloidosis? Clin Genet 57:430434, 2000
Polyglandular Endocrine Failure in a Patient With Amyloidosis Secondary to Familial Mediterranean Fever ¨ ztas, MD, Hakan Aksoy, MD, Neval Duman, MD, Bu¨lent Erbay, MD, Kenan Keven, MD, Erkin O and S¸ehsuvar Ertu¨rk, MD ● Familial Mediterranean fever (FMF) is 1 of the major causes of secondary amyloidosis. Renal involvement is the main clinical complication and it mostly presents with nephrotic syndrome and chronic renal failure. Although deposition of amyloid has been reported in several endocrine glands such as the adrenal, thyroid, and testes, clinically significant functional impairment is uncommon. Herein, we describe a patient in whom the diagnosis of FMF was based on molecular screening and who presented with recurrent hypoglycemic attacks and extensive amyloid deposition affecting various organ function including adrenal, thyroid, parathyroid, testes, intestinal system, and the heart. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Hypoglycemia; polyglandular endocrine failure; renal failure; secondary amyloidosis.
A
MYLOIDOSIS IS A systemic disease characterized by extracellular deposition of insoluble fibrillar proteins. Although primary amyloidosis is a plasma cell dyscrasia, secondary amyloidosis is associated with inflammatory or infectious diseases such as familial Mediterranean fever (FMF), tuberculosis, chronic osteomyelitis, and rheumatoid arthritis, in which the extensive deposition of amyloid A protein is distinctive.1,2 Secondary amyloidosis has been reported to involve the kidneys, adrenals, intestine, spleen, liver, and, less commonly, the thyroid, testes, stomach, and the heart. However, the main clinical presentation is renal complication.3,4 Clinically significant amyloid depositions in multiple organs rarely have been reported in secondary amyloidosis. Herein, we describe a patient with secondary amyloidosis who presented with severe hypoglycemic attacks, polyglandular endocrine failure, and severe intestinal involvement. CASE REPORT A 46-year-old man who had end-stage renal disease caused by secondary amyloidosis was admitted to Emergency Service because of acute seizures. He had been on maintenance hemodialysis treatment for 3 years. The history of the patient did not reveal any inflammatory or infectious disease that might lead to secondary amyloidosis. He had a history of chronic diarrhea for 5 years and mild pitting edema on the lower extremities for 2 years. Three years ago, chronic renal failure was diagnosed on a routine investigation before surgery for an inguinal hernia. After the surgery, the patient was referred to the Nephrology Department and he was found to have hypertension, 12 g/day proteinuria, hypoalbuminemia, and an elevated serum creatinine level. Gastroduodenoscopy and colonoscopy had been performed and mul-
tiple biopsies had been taken. There was severe atrophic changes in the intestinal mucosa. Congo red staining had revealed extensive amyloid deposition. Staining by antibody against serum amyloid A protein was positive. Three months later, the patient began chronic hemodialysis treatment 3 times a week. DNA testing was performed for FMF to find out the cause of the secondary amyloidosis. Mixed heterozygote status for M694V/M680I mutations was found at the 10 and 2 exons in the MEFV gene.5 The patient was prescribed colchicine 1 mg/day, however, he was reluctant to take the drug regularly. In recent months, the patient’s appetite decreased and his diarrhea increased. He lost his libido and became impotent. On physical examination, body mass index was 17 kg/m2, blood pressure was 100/60 mm Hg, pulse rate was 112/min, and he had a fever (38.5°C). The patient was unconscious and there were common thin rales and rhonchi in the lungs. Also, there was a diffuse hyperplasia in the thyroid. Laboratory evaluations revealed the following: blood glucose 22 mg/dL, blood urea nitrogen 65 mg/dL, serum creatinine 6.5 mg/dL, albumin 2.1 g/dL, total protein 4.1 g/dL, total cholesterol 34 mg/dL, triglycerides 45 mg/dL, uric acid, 6.2 mg/dL, calcium 7.1 mg/dL, phosphorus 3.1 mg/dL, sodium 137 mEq/L, potassium 3.9 mEq/L, hemoglobin 9 g/dL, leukocytes 7.700/mm3, and erythrocyte sedimentation rate 60 mm/h. The patient was treated with intravenous glucose and subcutaneous glucagon. He regained consciousness and felt better over the following hours, and was admitted to the
From the Departments of Nephrology and Urology, Ankara University Medical School, Ibni Sina Hospital, Ankara, Turkey. Received August 28, 2001; accepted as submitted August 31, 2001. Address reprint requests to Kenan Keven, MD, Yenibati mah. 284. sk, C4/6, Batikent, Ankara, 06370 Turkey. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 1523-6838/01/3806-0052$35.00/0 doi:10.1053/ajkd.2001.29295
American Journal of Kidney Diseases, Vol 38, No 6 (December), 2001: E39
1
2
KEVEN ET AL
nephrology department. The other laboratory evaluations were as follows: serum ferritin 321 ng/mL (the patient was on maintenance intravenous iron replacement), folic acid 4.5 ng/dL, vitamin B12 121 pg/mL, serum iron was 58 g/dL, total iron binding capacity was 150 g/dL, liver functions were normal, and viral markers including hepatitis B antigen, hepatitis C antibody, anti-cytomegalovirus (CMV) immunoglobulin (Ig) M, and human immune deficiency virus antibody were negative. Brain computed tomography (CT) showed no abnormality. Chest radiograph revealed pneumonic infiltration on the base of the right lung, and CT showed consolidation and pleural fluid on that side. Parenteral ceftriaxone was started for the lung infection. During the hypoglycemic attack, a blood sample had been taken for hormonal evaluations including insulin, C-peptide, adrenocorticotropic hormone (ACTH), plasma cortisol, thyroid-stimulating hormone (TSH), growth hormone (GH), and prolactin. Insulin level was 6.2 Iu/mL and C-peptide was 1.2 ng/mL. In other recurrent hypoglycemic attacks, similar insulin and C-peptide levels were measured. Because of persistent hypoglycemic attacks, the patient was treated with continuous dextrose infusion along with amino acid and lipid solutions. As shown in Table 1, though there was a response to hypoglycemia in the pituitary gland, no marked adrenal response was revealed. On the other hand, both serum-free T3 and T4 were below the normal range and TSH level was found to be elevated. Parathyroid hormone level was very low (0.85 pg/mL) despite lacking any history of either vitamin D or calcium treatments. Both amylase and lipase levels were within the normal range. Despite high levels of follicle-stimulating hormone (FSH) and leutinizing hormone (LH) levels, total and free testosterone levels were very low, indicating primary testicular pathology. Abdominal ultrasonography and CT, primarily focused on the pancreas and adrenal gland, showed no abnormality except bilaterally decreased renal size. Pituitary magnetic resonance imaging (MRI) showed no abnormality. After these laboratory investigations, ACTH stimulation test was performed with 1 mg depot tetracosactide (Synacten Depot, Ciba Geigy, Basel, Table 1.
Hormonal Status of the Patient on Admission
ACTH pg/mL (5–50) P-cortisol g/dL (6.2–19.4) FSH mIU/mL (1.5–9.7) LH mIU/mL (15–9.3) T. testosterone ng/dL (241–827) F. testosterone pg/mL (8.69–54.69) GH IU/mL (0–26) Sensitive TSH mIU/mL (0.35–5.5) F. T4 pmol/L (10–23) F. T3 pmol/L (2.8–7) Anti Tg IU/mL (0–50) AntiTPO IU/mL (0–15) Prolactin ng/mL (3.7–17.8) Parathormone pg/mL (9–55) Abbreviations: T, total; F, free. *Higher than normal range. †Lower than normal range.
307* 15.11 11.8* 16.5* 10.0† 0.63† 55.4* 18.7* 9.97† ⬍1.54† 2 5.5 100.6* 0.86†
Switzerland), and no significant response was observed. The thyroid was found to be mildly enlarged in ultrasonography and the testes were mildly reduced in size. Fine-needle aspiration biopsy of the thyroid and an open biopsy from the testes showed amyloid deposition. In testes tissue, staining with antibody against serum amyloid A protein was positive. Furthermore, echocardiographic examination was compatible with cardiac amyloidosis, showing restrictive cardiac involvement and typical granular sparkling of left ventricular myocardium. On the basis of the hormonal investigations, polyglandular endocrine involvement causing clinical significant primary hypothyroidism, primary adrenal failure, primary testicular failure, and hypoparathyroidism were diagnosed. After, completion of the hormonal tests, oral prednisolone was started at a dose of 15 mg/day and then dropped to 10 mg/day, oral L-thyroxine 50 g/day and intramuscular 250 mg testosterone propionate every 3 weeks were added subsequently. L-thyroxine was increased to 100 g/day. Parenteral vitamin B12 replacement was started. The patient felt better and the frequency of hypoglycemic attacks decreased. Control chest radiograph at day 15 of antibiotherapy showed resolution of pneumonia. After 3 weeks, the patient still had recurrent hypoglycemia and increased diarrhea. Furthermore, chronic diarrhea, very low lipid levels, and low vitamin B12 level were regarded as malabsorption owing to amyloid deposition, which was shown 3 years ago. For further evaluation of malabsorption, a microscopic examination of stool fat with 36% acetic acid and Sudan III was performed and there were lots of large orange globules representing free fatty acids. A D-xylose test was performed and the blood D-xylose level at the second hour of the test was 0.4 mg/dL, which was very low. Urinary D-xylose extraction could not be measured because of anuria. Total parenteral nutrition was administered for 5 days and prednisolone was given 10 mg/day. Blood glucose levels returned to the normal range, and then intravenous nutrition support was stopped. He was fed orally with glutamineenriched nutrition solution and supported with parenteral lipid and amino acid solutions during each hemodialysis session. Prednisolone dose was continued at 10 mg/day as a maintenance treatment. The patient was discharged and now he is on maintenance hemodialysis treatment without any hypoglycemic attacks.
DISCUSSION
We describe a patient with secondary amyloidosis presenting with severe hypoglycemic attacks. The patient had severe multisystem involvement causing end-stage renal disease, malabsorption, and polyglandular endocrine failure, including primary hypothyroidism, primary adrenal failure, primary testicular failure, and hypoparathyroidism. Cardiac involvement has also indirectly been shown by echocardiography. Despite the lack of any evidence related to FMF in the patient’s history, the patient has been shown to have FMF based on molecular testing.
HYPOGLYCEMIC ATTACKS IN AMYLOIDOSIS
Amyloidosis is a generalized disease and a common finding is renal involvement leading to renal failure and nephrotic syndrome. Less commonly, adrenal, thyroid, intestinal, pituitary, intestinal, and testicular involvements have been reported.6,7 Although, adrenal involvement has been shown to occur in 47% to 96% of patients with amyloidosis, primary adrenal failure caused by amyloidosis rarely has been reported. Arik et al7 reported subclinical adrenocortical failure in 7 of 12 patients with amyloidosis. In our case, the plasma cortisol level was measured under the hypoglycemic condition, which should be accepted as a stimulated level to endogenous increased ACTH level. Although the pituitary gland has adequately responded to hypoglycemia, there was no adrenal response. In addition, an exogenous ACTH stimulation test was performed to assess adrenal function and no marked increase was revealed. On the basis of these findings, subclinical adrenal failure could be overt during the pulmonary infection and both hypoglycemic attacks and hypotension on admission can be explained by adrenal failure. Testicular involvement causing hypogonadism was defined in few cases in the literature.6,8 The mechanism is complete replacement of all testicular structure by amyloid deposition. In our case, because of hypogonadism and a very low testosterone level, testicular amyloid deposition was considered and testes biopsy was performed. Staining of testes tissue with antibody against serum amyloid A protein was found to be positive. To the best of our knowledge, recurrent severe hypoglycemic attacks have not been reported in a patient with amyloidosis. In addition to adrenal failure, intestinal involvement might contribute to hypoglycemia. For the evaluation of absorption function of the intestine, microscopic examination of stool with Sudan III and D-xylose test were performed and severe malabsorption has been observed. The mechanism of the malabsorption is most likely the intestinal amyloid infiltration, which was shown 3 years ago. Therefore, severe malabsorption had an important role, inducing malnutrition in our patient. For the differential diagnosis, colchicine is a drug commonly used in the treatment of FMF, it inhibits epithelial crypt cell division and causes malabsorption, however, the patient was reluctant to take the
3
drug from the beginning of the diagnosis of FMF. Regarding endocrine disease as a cause of hypoglycemia, insulinoma was not likely the reason because both plasma insulin and Cpeptide levels were low during the hypoglycemic attack. Thyroid involvement has been reported to be 43.4% in systemic amyloidosis. Euthyroidism, hypothyroidism, and thyrotoxicosis can be seen in the patients.9,10 In our case, primary hypothyroidism was diagnosed and amyloid involvement was shown by fine-needle aspiration biopsy. In addition, though there was no therapy, which might have a suppressive effect on parathyroid function, the presence of hypoparathyroidism can also be explained by amyloid infiltration of parafollicular cells, however, more definite diagnoses necessitate histopathologic evidence. Although cardiac amyloidosis is a severe problem mainly for primary amyloidosis, it has also been reported in secondary amyloidosis.11,12 The patients might be asymptomatic or they might have symptoms of congestive heart failure. The echocardiography can show diffuse ventricular wall thickening, isolated septal wall thickening, and restrictive pattern of left ventricular diastolic function. Also, characteristic granular sparkling of left ventricular myocardium as seen in our patient is an important finding for cardiac amyloid involvement. In addition to this, our patient had restrictive involvement and mild left ventricular systolic dysfunction, possibly caused by cardiac amyloid deposition. Recently, a gene responsible for FMF was identified on chromosome 16 and the gene product pyrin or marenostrin was reported to be responsible for limiting the intensity of inflammation. The FMF-related mutations change the structure of the protein and impair the function, causing increased onset and persistence of inflammation.5 The cloning of the FMF gene (MEFV) now made it possible to establish a diagnosis of FMF even in patients lacking any evidence of the disease in their history. In literature, the 5 most common missense mutations were defined as M694V, M680I, V726A, and E148Q.13,14 Indeed, though our patient did not have any history related to FMF, he has been found to carry 2 heterozygote mutations for FMF (M694V, M680I). Initial studies have suggested that the presence of the M694V mutation carries a signifi-
4
KEVEN ET AL
cant risk for the development of amyloidosis. However, it has been shown that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient enough to explain the occurrence of amyloidosis in all patients with FMF.13,14 Nevertheless, more studies are needed to clarify the phenotypegenotype relation in patients with FMF amyloidosis. In conclusion, severe hypoglycemic attacks can be a finding of severe diffuse secondary amyloidosis affecting endocrine and intestinal organs. REFERENCES 1. Cohen AS, Connors LH: The pathogenesis and biochemistry of amyloidosis. J Pathol 151:1-10, 1987 2. Kuhlback B, Wegelius O: Secondary amyloidosis. Acta Med Scand 180:737-745, 1966 3. Triger DR, Joekes AN: Renal amyloidosis-a fourteenyear follow-up. QJM 165:15-40, 1973 4. Brandt K, Cathcart ES, Cohen AS: A clinical analyses of the course and prognosis of forty-two patients with amyloidosis. Am J Med 44:955-969, 1968 5. The International FMF Consortium: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797807, 1997 6. Handelsman DJ, Yue DK, Turtle JR: Hypogonadism
and massive testicular infiltration due to amyloidosis. J Urol 129:610-612, 1983 7. Arik N, Tasdemir I, Karaaslan Y, Yasavul U, Turgan C, Caglar S: Subclinical adrenocortical insufficiency in renal amyloidosis. Nephron 56:246-248, 1990 8. Schrepferman CG, Lester DR, Sandlow JI: Testicular amyloid deposition as a cause of secondary azoospermia. Urology 55:145, 2000 9. Erturk S, Duman N, Ates K, Ekinci C, Erbay B, Karatan O, Erdogan G, Ertug E, Dizbay Sak S: Amyloid deposition in the thyroid gland in patients with amyloidosis: An incidence study with fine-needle aspiration biopsy of the thyroid. Nephrol Dial Transplant 10:1473, 1995 10. Duhra P, Cassar J: Thyroid function tests in amyloid goitre. Postgrad Med J 66:304-306, 1990 11. Cacoub P, Axler O, De Zuttere D, Hausfater P, Amoura Z, Walter S, Wechsler B, Godeau P, Piette J: Amyloidosis and cardiac involvement. Ann Med Interne (Paris) 151:611617, 2000 12. Moyssakis I, Triposkiadis F, Rallidis L, Hawkins P, Kyriakidis M, Nihoyannopoulos P: Echocardiographic features of primary, secondary and familial amyloidosis. Eur J Clin Invest 29:484-489, 1999 13. Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E: MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 6:1-6, 1999 14. Tekin M, Yalcinkaya F, Cakar N, Akar N, Misirlioglu M, Tastan H, Tumer N: MEFV mutations in multiplex families with familial Mediterranean fever: Is a particular genotype necessary for amyloidosis? Clin Genet 57:430434, 2000