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Familial renal amyloidosis
Familial Renal Amyloidosis Case Reports, Literature Review and Classification
FRED ALEXANDER,
M.D.
E. LAURENCE ATKINS, M.D. Calgary, Alberta,
Canada
Three siblings (two brothers and a sister) of Polish origin, presented in late middle age with the features of the nephrotic syndrome and hypertension. Glomerular deposition of amyloid was found in all on renal biopsy. No amyloid was seen on rectal or gingival biopsy. Their mother and a maternal aunt died in middle age with a clinically similar disease. These cases are compared with other forms of hereditary amyioidosis which are briefly reviewed. The hereditary amyloidoses are classified with particular emphasis on neural and renal involvement. Amyloidosis occurring in association with persistent chronic inflammatory disease and plasma cell disorders is well known [ 1,2]. Primary amyloidosis is rare, and the hereditary amyloidosis syndromes are poorly recognized except for familial Mediterranean fever ]3] and Portuguese neuropathy [ 41. In the past, the hereditary amyloidoses have been classified according to the presence or absence of neural involvement [5]. A review of the literature reveals a number of reports of prominent renal involvement [3,6-g] in the nonneuropathic group. Our purpose is to present a family with the nephrotic syndrome, hypertension and renal amyloidosis, and to focus attention on renal involvement as well as neural involvement in familial amyloidosis. The syndrome in this family may represent a new variety of hereditary amyloidosis; this is the first report of familial renal amyloidosis in a non-Jewish family of Polish extraction. The clinical and pathologic features are compared with those in previously reported forms of hereditary amyloidosis. The hereditary amyloidoses are discussed and a new classification is presented.
CASE REPORTS Case 1. This 58 year old man (V.S.) was admitted to the Foothills Hospital, Calgary, on November 15, 1968, for investigation and treatment of hypertension
and renal insufficiency.
in a small Southern cough. From the Departments of Pathology and Medicine, The University of Calgary Medical School and Foothills Hospital, Calgary, Alberta, T2N 2T9 Canada. Requests for reprints should be addressed to Dr. F. Alexander, Division of Pathology, The University of Calgary Medical School. Calgary, Alberta T2N 2T9 Canada. Manuscript accepted May 21. 1974.
Alberta
His blood pressure
He had presented
town about 2 weeks was 210/120
to his family doctor
earlier
with diarrhea
and
mm Hg. The urine test revealed
4+
proteinuria. His hemoglobin level was 10 g/100 ml. By the time he was admitted, he was feeling reasonably well. He denied any headaches. He had lost about 15 pounds in weight. He had not had any chest pain, but he had a persistent
cough which was productive
little sputum. He blamed this on the fact that he had worked for many years. He had never been seriously ill before.
July 1975
of a
in coal mines
His mother had died from kidney
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FAMILIAL
RENAL AMYLOIDOSIS-ALEXANDER,
ATKINS
disease at the age of 50 years. He had seven siblings, one of whom, a sister, also had kidney disease and high blood pressure. The patient was married and had 10 children who were all well. His only other complaint was polyuria, which had been present for several years. He had never had any edema or discoloration of his urine. On physical examination, he appeared ill. His complexion was sallow. The blood pressure was 240/120 mm Hg. Funduscopic examination revealed arteriolar tortuosity and some A-V nicking but no hemorrhages or exudates. He had a large palpable thyroid which was firm and nontender. There was no lymphadenopathy. His chest was clear, and the heart sounds were normal. No abdominal masses were felt. Laboratory investigations are presented in part in Table I. Urine specific gravity was 1.012, and several hyalin and coarsely granular casts were seen. Urine culture was negative. 17-ketosteroids were 10.2 mg/24 hours, and 17hydroxycorticosteroids were 8.5 mgJ24 hours. An immunoglobulin assay showed the immunoglobulin A (IgA) level to be 500 mg/lOO ml, immunoglobulin G (IgG) level 2,220 mg/lOO ml and the immunoglobulin M (IgM) level 64 mg/ 100 ml. Only the IgG level was considered to be elevated. Triiodothyronine level was 24.8 per cent. The plasma cortisol level was 16 pug/100 ml at 1000 hours and 12 pg/lOO ml at 2030 hours. A Mantoux test was positive at 1 in 10.000 dilution. Sputum cultures were negative for acidfast bacilli. No thyroid antibodies were isolated. The creatinine clearance was 17.5 ml/min. Electrocardiogram showed left ventricular hypertrophy. An intravenous pyelogram was interpreted as showing diminished concentration, but there was no abnormality on tomography of the kidneys. A bone marrow biopsy was carried out on December 13, 1968, and this was normal. A needle biopsy specimen of the thyroid, obtained on December 6, 1968, showed chronic thyroiditis. On November 29, 1968, needle biopsy of the right kidney revealed the presence of amyloid. The hypertension was controlled with methyldopa, 500 mg daily, and hydrochlorothiazide, 50 mg daily. The patient was readmitted to the Foothills Hospital in January 1970, with increasing fatigue, weakness, shortness of breath and generalized pruritus. Physical findings were as on the first admission except for a fall in blood pressure which was 1901105 mm Hg. The hemoglobin level was 8.8 g/100 ml, and the blood urea nitrogen level had risen to 89 mg/lOO ml with a serum creatinine level of 6.2 mg/lOO ml. The serum complement level was normal. Creatinine clearance was 14 ml/min. The protein content of a 24 hour urine collection was 4.6 g. An x-ray film of the chest showed fine nodular densities in both lungs, particularly in the upper lobes which had changed little since the previous admission. Gingival and rectal biopsies did not reveal any amyloid. The patient was readmitted to the Foothills Hospital on April 22, 197 1; he died 5 days later. His hemoglobin level was 6.0 g/ 100 ml, serum creatinine 18.0 g/100 ml and blood urea nitrogen 192 mg/lOO ml.
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The American Journalof Medicine Volume 59
Pathologic Findings Histologic examination of the biopsy specimen of the right kidney showed almost complete replacement of all the glomeruli by amyloid. There was extensive obliteration of the capillary lumens and a reduction in glomerular cellularity. The presence of amyloid was confirmed by methyl violet, Congo red and thioflavine-T stains. Associated with this loss of glomeruli, there was marked tubular atrophy and a moderate increase in interstitial fibrous tissue. No significant interstitial inflammation was present. Amyloid was not found in vessels, tubular basement membranes or interstitial tissue. Many of the tubules contained proteinaceous casts. Postmortem external examination revealed only an enlarged thyroid and edema of the feet and ankles. There were 150 ml of straw-colored fluid in each pleural cavity and some firm fibrous adhesions between visceral and parietal pleura over the upper lobes. In the lungs there were several firm to hard anthracotic nodules. The heart weighed 500 g and showed left ventricular hypertrophy. The liver weighed 1,340 g and was not firm or markedly congested. The spleen weighed 300 g. It was dark brown in color and of slightly firm consistency. Subcapsularly, a paler area was present. The right kidney weighed 130 g, the left 135 g. Both were firm, and the cortices appeared pale and waxy. No other lesion was found except for diverticulosis in the pelvic colon. The thyroid was pale, firm and nodular. Histologic examination confirmed the presence of a few silica-anthracotic nodules in the lungs. The thyroid contained a considerable quantity of fibrous tissue and a heavy lymphoid infiltrate without germinal centers. The main findings were deposition of amyloid confined to the kidneys, adrenals and spleen. No amyloid could be detected in any other tissue including liver, intestine, lymph node, peripheral nerve, subcutaneous tissue, heart and tongue. In the kidneys, the amyloid was as previously described in the biopsy specimen, but a few irregularly defined deposits of amyloid were also present in the medullary interstitial tissue. Blood vessels were not obviously involved in the cortex and could not be identified in the medullary nodules. In the adrenal glands, the amyloid was in the region of the zona reticularis mainly. The amyloid in the spleen did not involve the Malpighian bodies but formed a thick irregular layer on the inner aspect of the capsule. Many of the trabeculas were converted to thick bands of amyloid. Hemosiderin pigment was prominent in the splenic sinusoids. Special stains confirmed the presence of amyloid as described with no staining in other organs. Electron microscopy showed the typical fibrillar structure of the amyloid in the kidney. Case 2. A 54 year old man (A.S.) (brother of V.S., Case 1) was admitted to the Foothills Hospital on May 11, 1969, for investigation of proteinuria and hypertension. The proteinuria had been noted 3 years earlier, and for the past year there had been some swelling of his hands and feet. His only complaint was nocturia twice nightly. A few months prior to admission, he had been given Aldomet@, 500 mg daily, for hypertension. The patient had been born
FAMILIAL
in a small town in Southern Alberta, was single and worked as a ranch hand. The findings on physical examination were unremarkable except for slight pallor. Two linear hemorrhages were seen in the right fundus, but there was no other retinopathy. The blood pressure was 220/l 10 mm Hg. The liver was barely palpable. A sigmoidoscopic examination was within normal limits. Laboratory investigations are presented in part in Table I. Bence Jones protein was not found. Urinary steroid values were normal. An electrocardiogram showed left ventricular hypertrophy. A renal biopsy was carried out on May 15, 1969. The patient was discharged on antihypertensive medication; it was later learned that he died of renal failure in another hospital in February 1970. Gingival and rectal biopsies had been performed, but an autopsy had not been carried out.
Pathologic Findings No histologic abnormality was detected in the rectal or gingival biopsy specimens. Amyloid stains were negative. The kidney biopsy specimen showed cortex and medulla. The glomeruli were largely replaced by nodular and diffuse areas of amyloid deposition. Some tubular atrophy was observed but no amyloid was detected with special stains in vessels outside the glomeruli, tubules or interstitial tissue. Case 3. This 48 year old woman (M.L.) (a sister of VS., Case 1) first became ill in 1967 with the sudden onset of edema of her legs. She also had headaches, general malaise and nausea and was treated with antihypertensive medication. Proteinuria was detected initially in 1960 during her pregnancy. She had been married on two occasions. There were four children from her first marriage and one from the second marriage. Physical examination revealed a blood pressure of 160/ 100 mm fig. Her fundi showed only grade I retinopathy with mild arteriolar narrowing and no hemorrhages or exudates. The liver and spleen were not palpable, and there was no peripheral edema. The patient was admitted to the Foothills Hospital in January 1969 for further investigation of proteinuria, hypertension and renal insufficiency. The protein content of a 24 hour urine collection was 6.5 g. The serum creatinine was 4.0 mgf 100 ml with a blood urea nitrogen of 50 mg/ 100 ml. The serum proteins were 5.5 g/100 ml with a slightly abnormal electrophoretic pattern showing a small unidentified band between the beta and gamma globulin. Urine steroid levels were normal. Creatinine clearance was 12 ml/min. Renal and rectal biopsies were carried out. It was learned later that this patient died in another hospital of renal failure. An autopsy was not obtained. Pathologic Findings The glomeruli in the kidney biopsy specimen were almost completely replaced by homogeneous hyaline material staining positively for amyloid with methyl violet, Congo red and thioflavine-T. The tubules were mildly atrophic in
RENAL AMYLOIDOSIS-ALEXANDER.
ATKINS
areas, whereas a few were dilatea and contained proteinaceous casts. A few small focal accumulations of amyloid were identified in the interstitial tissue. No amyloid could be identified in blood vessels. The rectal biopsy specimen was negative for amyloid. Case 4. This patient (A.B.) (a maternal aunt of V.S., Case 1) died in 1964 at the age of 53. The final diagnosis was “chronic nephritis” with hypertension, edema and proteinuria. No autopsy was performed. She had first become ill early in 1953 at the age of 42 and was admitted to the hospital with proteinuria, urinary frequency, listlessness and tiredness. In April 1953, she was readmitted with “albuminuria,” and edema of the feet, ankles and eyelids. Blood pressure was recorded as 169/ 95 mm Hg. In 1959, she underwent a hemorrhoidectomy, and a diagnosis of “chronic nephritis” was also made at that time. Her blood pressure was recorded as high as 204/122 mm Hg. In June 1961, she reentered the hospital with “kidney trouble,” edema of her legs and headache. She had been taking diuretics for the previous 7 years. Blood pressure was 180/ 110 mm Hg and blood urea nitrogen 75 mg/ 100 ml. The patient’s final admission was in February 1964. Her chief complaints were weakness, dyspnea and ankle edema. She was pale with pitting edema to her knees. The optic fundi had arteriolar tortuosity and old hemorrhages were present. A diagnosis of uremia and chronic nephritis with secondary hypertension was made. The hemoglobin level was 5.6 g/l 00 ml, blood urea nitrogen 108 mg/ 100 ml, proteinuria 3-t, total carbon dioxide 44 meq/liter and blood pressure 180/l 10 mm Hg. Despite the administration of blood transfusions and diuretics, she became increasingly uremic, confused and dyspneic and died on March 29, 1964. Case 5. This patient (A.S.M.) (the mother of V.S., Case 1) died in St. Vincent’s Hospital, Pincher Creek, Alberta, on September 4, 1938, at the age of 46. No autopsy was performed, and the hospital records at that time were very sketchy. However, the physician’s comment was that she had suffered from “Bright’s disease” for 2 years, had high blood pressure and albuminuria. Her initial complaints were headache,’ weakness and dyspnea. She was born in Poland and came to Canada at an early age. She had been married twice and had 10 children, 6 from the first marriage and 4 from the second. Her parents apparently lived to be elderly, and there was no previous history of kidney disease in the family. COMMENTS Amyloid disease is recognized as occurring in primary and secondary forms. The latter is generalized in distribution and found in association with persistent chronic inflammation. The primary form may be generalized or involve a single organ-isolated organ amyloidosis. It may occur as sporadic cases or in a hereditary form. The best known examples of hereditary amyloidosis are Portuguese amyloid neuropathy
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FAMILIAL RENAL AMYLOIDOSIS-ALEXANDER.
TABLE
I
Clinical and Laboratory Data
ATKINS
Findings on Admission
Case 1
Sex Blood pressure (mm Hg) Hemogloblin (g/100 ml) Edema Serum proteins (g/100 ml) Serum albumin (g/100 ml) Urinary protein/24 hours Serum immunoglobulins Serum creatinine (mg/lOO Blood urea nitrogen (mg/IOO ml) Liver function tests Serum cholesterol
Case 2
Case 3
M 210/120 11.6
M 220/110 9.7
F 160/100
+ 7.6 2.9 5.1
+ 4.3 1.8 9.2 Normal
+ 5.5 2.6 6.5 ...
f fgG
ml)
4.8
9.5
3.4
60
3.8
54
44
Normal 170
Normal 337
Normal 260
Yes
Yes
Yes
+ -
+
-
...
Absent
Absent
(m&100 ml) Death from renal failure Amyloid on renal biopsy Amyloid on rectal biopsy
+ -atau-
Amyloid
-at
on gingival
biopsy
topsy Absent
Fever, neuropathy, skin eruption, abdominal pain, eye lesions NOTE:
+ = positive;
-
=
topsy au-
negative.
[4] and familial Mediterranean fever [3], the former being a predominantly neuropathic form and the latter predominantly non-neuropathic. The familial nature of the disorder we describe is indicated by the similarity in the clinical and laboratory findings in the three siblings (Tables I and II). All three presented with proteinuria more than 5 g/24 hours, hypoproteinemia and edema, i.e., a nephrotic presentation. Renal biopsy in each case demonstrated amyloid which was almost exclusively observed within glomeruli. Hypertension was noted and all three siblings died from renal failure, as did their mother and a maternal aunt. The onset, or more accurately, the age of presentation, was in the 5th or 6th decade in each case, and the age at death ranged from 46 to 60 years. The family tree is shown in Figure 1. The most striking features exhibited by these siblings were the renal amyloidosis and the prominence TABLE
Chronology
II
of the Renal Disease
1
2
3
4
5
Average
VS. 58
A.S. 52
M.L. 42
A.B. 42
A.S.M. 44
47.6
60 2
55 3
49 7
51 9
46 2
+
+
+
+
+
Case Case Case Case Case Data Patients initials Age at presentation (yr) Age at death (yr) Duration of illness Death from renal failure
j24
July 1975
(yr)
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of clinical features related to kidney disease. Renal amyloidosis is common in so-called secondary amyloidosis, but no predisposing cause was found in these cases. There was no history of chronic infection or inflammatory disease and although the serum IgG level was elevated in Case 1, there was no plasmacytosis and no cause found at postmortem examination. Serum immunoglobulin levels were normal in Case 2. The finding of amyloid in the kidneys of patients with hereditary amyloidosis is common, even though the principal manifestations of the disorder are less frequently related to the renal involvement. In Portuguese amyloid neuropathy, the renal amyloid is usually in the medulla and clinically insignificant. Nephropathy was also present in all but one of the pathologically verified familial amyloidosis cases of Van Allen [lo], although it was variable in quantity and distribution. Large vessel involvement by amyloid resulted in renal atrophy, and in several cases there was little amyloid in the renal cortex. Uremia was the most common cause of death, and the nephrotic state did not occur. Meretoja and Teppo [ 1 l] reported marked glomerular amyloid deposits in their cases of familial amyloidosis with cranial neuropathy. In patients with familial Mediterranean fever, Heller et al. [3] described 47 of 141 patients as having clinical renal disease, and in those coming to autopsy, there were particularly striking glomerular amyloid deposits. Severe renal involvement was also observed in the heredo-familial amyloidosis cases of Muckle and Wells [6]. Proteinuria was described in semiquantitative terms only (“large quantities,” “massive”), and the patients were not described as nephrotic. Death was often considered to be due to renal failure. Ostertag [S] observed nephropathy with albuminuria and hematuria progressing to renal failure in a mother, three children and a grandchild. Amyloidosis was widespread in the two members examined at autopsy and involved the kidneys. Maxwell and Kimbell [7] reported amyloid in the kidneys of three brothers, and nephropathy was the principal manifestation of amyloidosis in a Swedish family with pathoanatomic findings identical to those of familial Mediterranean fever
t91. Mahloudji et al. [6] discussed hereditary amyloidosis in neuropathic, non-neuropathic and localized forms. He considered three types of hereditary neuropathic amyloidosis: Type I Andrade (Portuguese), type II Rukavina (Indiana) and type Ill Van Allen (Iowa). The basic difference in these three forms lies in the distribution of the neuropathy-feet, hands and feet, and hands, respectively. He described a large Maryland kindred with a condition similar to type II Rukavina amyloid neuropathy. A number of reports of amyloid neuropathy in Japan [ 12,131 document a
FAMILIAL
RENAL AMYLOIDOSIS-ALEXANDER,
ATKINS
I
Figure 1. Family pedigree.
disease which is very similar to type I Andrade (Portuguese). Meretoja [ 141 and Meretoja and Teppo [ 1 l] described a further variety of familial amyloidosis with cranial nerve involvement as the principal manifestation. They called this a third type of familial amyloidosis with polyneuropathy, but omitted the well recognized Van Allen (Iowa) type. It should therefore be considered type IV, if one wishes to type them in this way. Hereditary amyloidosis of predominantly non-neuropathic type was first described by Ostertag [6,15]. The features included renal failure, hypertension and hepatosplenomegaly with autosomal dominant inheritance. In 1961, Heller et al. [S] described amyloidosis in familial Mediterranean fever, which is characterized by recurrent bouts of fever, arthritis and abdominal pain. Amyloidosis has been described as the sole manifestation of familial Mediterranean fever [ 161, and the disease has been divided into two phenotypes. In phenotype 1 the classic features are observed whereas in phenotype 2, amyloidosis is observed as the first clinical manifestation or sole manifestation. A new heredo-familial syndrome of urticaria, deafness and amyloidosis was reported by Muckle and Wells [8]. This condition starts during adolescence with chills, malaise and transient attacks of urticaria. Progressive deafness and nephropathy due to amyloidosis develop. This is a rare disorder, the fourth recorded study being presented by Black [ 171
in 1969. Other rare forms of non-neuropathic hereditary amyloidosis include a Russian family with allergic troubles and renal failure [ 181, cardiac amyloidosis [ 191 and hereditary cerebral hemorrhage and amyloidosis of cerebral vessels [20]. Less well documented cases of probable familial amyloidosis include those of Maxwell and Kimbell [7] followed up in 1967 as recorded by Mahloudji et al. [6] and the family described by Bergman and Warmenius [9] in Sweden. Renal involvement was marked in both these families. Mahloudji et al. [5] include a family with cold hypersensitivity and amyloid in the thyroid of one patient. No other material has been studied for the presence of amyloid in this family. The same patient was reported to have pinnal calcification associated with cold hypersensitivity by McKusick and Goodman [21]. Localized forms of hereditary or familial amyloidosis include medullary carcinoma of thyroid and pheochromocytoma [22] and varieties of cutaneous amyloid [23-261. Lattice cornea1 dystrophy was considered to be a localized form [27], but renal biopsy showed amyloid in glomeruli [28]. From the foregoing discussion it is obvious that renal involvement is the most prominent finding in many types of non-neuropathic hereditary amyloidosis. We, therefore, propose a classification of hereditary amyloidosis into neuropathic, nephropathic, miscellaneous and localized (Table Ill).
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TABLE
III
Classification
of Familial
Classification
Alternate
Amyloidosis
Names
Ethnic Origin
Type I (Andrade) Type II (Rukavina) Neuropathic
form
Principal Manifestation Lower extremity Upper extremity
Portuguese and Japanese Swiss and German (Indiana, Maryland) Scottish-English, Irish
Type III (Van Allen)
Mixed
neuropathy neuropathy
upper and lower extremity
neuropathy
(Iowa) Type IV Heller et al. [3] familial Mediterranean fever Muckle, Wells [8] Ostertag Nephropathic form
Cranial
Finnish Jews, Armenians, generally English
[6]
Fever, abdominal or chest neuropathy Urticaria, deafness
Arabs
German
[9]
Swedish
Vinogradova et al. [18] Alexander, Atkins (present study)
pain,
arthritis
Nephropathy, hypertension, hepatosplenomegaly Chills and fever in childhood; nephropathy Abdominal pain, fever in childhood; nephropathy Allergies, renal failure Nephrotic syndrome, hypertension, renal failure
?
Maxwell, Kimble (71 Bergman, Warmenius
neuropathy
Russian Polish
Familial amyloid heart disease [19] Hereditary cerebral hemorrhage with amyloidosis [20] Lattice cornea1 dystrophy
Miscellaneous
F'7281 Cutaneous amyloid 123-261 Medullary carcinoma of thyroid and pheochromocytoma 1221
Localized
TABLE
IV
Comparison
of Features
in Recorded
Ostertag [6J Presentation
Cases and Present
Maxwell,
CASE 1: Poststreptococcal nephritis (age 31); hepatosplenomegaly
Kimball
[71
Bergman, Warmenius
CASE 1: Chills and fever in childhood; pain in kidney region; chronic rhinitis
(age 33)
CASE 2: Diphtheria, proteinuria (age 22); nephritis, headache, hypertension, proteinuria and casts (age 24); hepatosplenomegaly
Study Alexander, Atkins (present study) ~~.~ _._ CASE 1: Hypertension; nephrotic syndrome
[9]
CASE 1: Frequent attacks of abdominal pain, fever and nausea; scarlet fever (age 5); persistent proteinuria
(age 58)
(age 22) CASE 2: Frequent attacks of abdominal pain, fever and nausea; scarlet fever (age 10); persistent proteinuria
CASE 2: Chills and fever in childhood; pain in kidney region CASE 3: Chills and fever in childhood; pain in kidney region
CASE 2: Nephrotic syndrome; hypertension (age 52) CASE 3: Nephrotic syndrome; hypertension (age 42)
(age 14)
(age 25) Age at death
Organs involved by amyloid Liver Spleen
CASE 1: 45 CASE 2: 43 CASE 3: 43
CASE 1: 35 CASE 2: 39
(yr)
CASE 1
CASE 2
CASE 1
CASE 2
CASE 3
CASE 1
CASE 2
+
+
...
+
+
(2 kg) +
...
+ +
+ +
+ +
+ (4.6 kg) +
Kidneys Adrenals Others NOTE: T.B. = caseous
+ + +
(6Tg)
(2.:kg)
(95Tg) + + +
(9Oig) + + ...
tuberculosis;
+ = present;
(2.3+kg)
... -
CASE 1: 35 CASE 2: 21
-
= absent;
+T.B.
+
. , . = unknown.
+
1::
CASE 1: 60 CASE 2: 55 CASE 3: 49
CASE 1 -
CASE 2
CASE 3
...
. .
(3OTg)
..’ +
‘.. +
_’
‘i
+ +
_
or
FAMILIAL RENAL AMYLOIOOSIS-ALEXANDER
Do the cases presented in this report represent a new variety of familial amyloidosis? There were no neuropathic symptoms and the nerves were not involved by amyloid at autopsy, so they would not fit into the group of hereditary amyloidosis of predominantly neuropathic type. The absence of (1) the clinical features of familial Mediterranean fever in these patients or their relatives, (2) urticaria and deafness, (3) allergies, (4) progressive cardiac failure, (5) cerebral hemorrhage and (6) cornea1 dystrophy exclude them from these six types. We are, therefore, left with the early cases of Cstertag [6,15], Maxwell and Kimble [7] and the more recent cases of Bergman and Warmenius [9] to consider. The important features are presented in Table IV. The presentation in the cases described by Bergman and Warmenius [9] is very similar to that in familial Mediterranean fever, and pathoanatomic findings are identical. These patients may represent a variety of this syndrome, despite their Swedish origin. Familial Mediterranean fever has been described in an Italian family [29] and in members of other ethnic groups around the Mediterranean (French [four], Spanish [three], Italian [three], Greek [two], Iranian [one]) and also from Sweden [four] and Holland [one] [30]). Th ey d’ff I er f rom this report in their clinical presentation and the generalized nature of the amyloidosis. The patients of Ostertag [6] differ from those we describe in their clinical presentation and distribution of amyloid. Noteworthy differences are the diagnosis of nephritis in both patients (although exactly what is meant by nephritis is uncertain), hepatosplenomegaly and massive involvement of the liver by amyloid. However, the relatively scanty information available on these patients makes a thorough comparison difficult.
ATKINS
The three brothers described by Maxwell and Kimbell [7] are similar in their predominantly renal symptoms to the siblings we describe, but attacks of chills and fever were also noted in childhood. A son of one of the brothers had the same childhood symptoms plus a skin rash and died of renal amyloidosis at age 39. Two of his children have had frequent bouts of fever with severe transient joint pains and maculopapular rashes. No deafness was observed in any members of this kinship. None of the three brothers had hypertension; all had amyloid in the liver and one of them had disseminated caseous tuberculosis. The distinctive features of the family reported here are the pure renal symptoms-an insidious onset of nephrotic syndrome and hypertension. No fevers, chills or rashes have been observed in any of their children. The distribution of amyloid is confined to the kidneys, spleen and adrenals. The distribution of the amyloid in the spleen with marked involvement of the capsule and subcapsular area is also unusual. The patients are of Polish extraction, an ethnic group in which we have been unable to find a report of familial amyloid nephropathy. We, therefore, believe that they justify inclusion as having a further variety of familial renal amyloidosis. Study of the following generation as they reach middle age will help to define this entity more clearly.
ACKNOWLEDGMENT We wish to thank Dr. D. J. Goddard and Dr. M. R. Hodgson of Pincher Creek, Alberta. Their cooperation and assistance in clinical follow-up was essential to the case studies of these patients. Thanks are also expressed to Dr. R. Lannigan, Professor and Head, Division of Pathology, The University of Calgary, for his helpful criticism and advice.
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Muckle TJ. Wells M: Urticaria, deafness and amylokfosis. A new he&o-familial syndrome. Q J Med 31: 235. 1962. Bergman F. Warmenius S: Familial perireticular amyloidosis in a Swedish family. Am J Med 45: 601, 1988. Van Allen MW, Frohlich JA. Davis JR: Inherited predisposition to general&d amyloiosis. Clinical and pathological study of a family with neuropathy, nephropathy and peptic ulcer. Neurology 19: 10, 1969. Meretoja J, Teppo L: Histopathological findings of familial amyloklosis with cranial neuropathy as principal manifestation. Report of three cases. Acta Pathol Microbial Stand 79-A: 432. 1971. Nakagawa S, Suzue K: Amyloiiosis in Japan. Pathol Microbiol (Basel) 27: 850, 1964. Araki S, Mawatari S, Ohta M: Polyneuritic amyloidosis in a Japanese family. Arch Neural 18: 593, 1968. Meretoja J: Familial systemic paramyloidosis with lattice
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FAMILIAL RENAL AMYLOIOOSIS-ALEXANDER, ATKINS
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dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms. A previously unrecognised heritable syndrome. Ann Clin Res 1: 314, 1969. Ostertag B: Familiire Amyloid-Erkrankung. 2 Menschl Vererb Konstitionslehre 30: 105, 1950. Blum A, Gafni J, Sohar E, Schibolet S, Heller H: Amyloidosis as the sole manifestation of familial Mediterranean fever. Further evidence of its genetic nature. Ann Intern Med 57: 795, 1962. Black JT: Amyloidosis, deafness, urticaria and limb pains: a hereditary syndrome. Ann Intern Med 70: 989, 1969. Vinogradova OM, Tareeva IE, Serov VV, Borisov IA: The primary family amyloidosis. Therap Arch 41: 105, 1969. Frederiksen T, Gotzsche H, Harboe N, Kiaer W, Mellemgaard K: Familial primary amyloidosis with severe amyloid heart disease. Am J Med 33: 328, 1962. Grdmundsson G, Hallgrimsson J, Jonasson TA, Bjarnason 0: Hereditary cerebral hemorrhage with amyloidosis. Brain 95: 387, 1972. McKusick VA, Goodman RM: Pinnal calcification. Observations in systemic diseases not associated with disordered calcium metabolism. JAMA 179: 230, 1962. Schimke RN, Hartmann WH: Familial amyloid-producing
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28.
29. 30.
medullary thyroid carcinoma and pheochromocytoma. A distinct genetic entity. Ann Intern Med 63: 1027. 1965. lsaak L: Localised amyloidosis cutis with psoriasis in siblings. Arch Dermatol61: 859, 1950. Souza AR: Amiloidose cutannea bolhosa familial. Rev Hosp Clin Fat Med (Sao Paula) 18: 413. 1963. Tay CH: Genodermatosis in Singapore. Asian J Med 7: 413, 1971. Rajogopalen K, Tay CH: Familial lichen amyloidosis. Report of 19 cases in 4 generations of a Chinese family in Malaysia. Br J Dermato187: 123, 1972. Klintworth GK: Lattice cornea1 dystrophy, an inherited variety of amyloidosis restricted to the cornea. Am J Pathol 50: 371, 1967. Meretoja J, Jokinen EJ, Collan Y, Lahdevirta J: Renal biopsy findings in familial amyloidosis with cornea1 lattice dystrophy. Acta Pathol Microbial Stand 80A (suppl 223): 228, 1972. Reich CB, Franklin EC: Familial Mediterranean fever in an ltalian family. Arch Intern Med 125: 337, 1970. Sohar E. Gafni J, Pras M, Heller H: Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43: 227, 1967.
FRED ALEXANDER,
M.D.
E. LAURENCE ATKINS, M.D. Calgary, Alberta,
Canada
Three siblings (two brothers and a sister) of Polish origin, presented in late middle age with the features of the nephrotic syndrome and hypertension. Glomerular deposition of amyloid was found in all on renal biopsy. No amyloid was seen on rectal or gingival biopsy. Their mother and a maternal aunt died in middle age with a clinically similar disease. These cases are compared with other forms of hereditary amyioidosis which are briefly reviewed. The hereditary amyloidoses are classified with particular emphasis on neural and renal involvement. Amyloidosis occurring in association with persistent chronic inflammatory disease and plasma cell disorders is well known [ 1,2]. Primary amyloidosis is rare, and the hereditary amyloidosis syndromes are poorly recognized except for familial Mediterranean fever ]3] and Portuguese neuropathy [ 41. In the past, the hereditary amyloidoses have been classified according to the presence or absence of neural involvement [5]. A review of the literature reveals a number of reports of prominent renal involvement [3,6-g] in the nonneuropathic group. Our purpose is to present a family with the nephrotic syndrome, hypertension and renal amyloidosis, and to focus attention on renal involvement as well as neural involvement in familial amyloidosis. The syndrome in this family may represent a new variety of hereditary amyloidosis; this is the first report of familial renal amyloidosis in a non-Jewish family of Polish extraction. The clinical and pathologic features are compared with those in previously reported forms of hereditary amyloidosis. The hereditary amyloidoses are discussed and a new classification is presented.
CASE REPORTS Case 1. This 58 year old man (V.S.) was admitted to the Foothills Hospital, Calgary, on November 15, 1968, for investigation and treatment of hypertension
and renal insufficiency.
in a small Southern cough. From the Departments of Pathology and Medicine, The University of Calgary Medical School and Foothills Hospital, Calgary, Alberta, T2N 2T9 Canada. Requests for reprints should be addressed to Dr. F. Alexander, Division of Pathology, The University of Calgary Medical School. Calgary, Alberta T2N 2T9 Canada. Manuscript accepted May 21. 1974.
Alberta
His blood pressure
He had presented
town about 2 weeks was 210/120
to his family doctor
earlier
with diarrhea
and
mm Hg. The urine test revealed
4+
proteinuria. His hemoglobin level was 10 g/100 ml. By the time he was admitted, he was feeling reasonably well. He denied any headaches. He had lost about 15 pounds in weight. He had not had any chest pain, but he had a persistent
cough which was productive
little sputum. He blamed this on the fact that he had worked for many years. He had never been seriously ill before.
July 1975
of a
in coal mines
His mother had died from kidney
The Amerfcan Journal of Medicine
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121
FAMILIAL
RENAL AMYLOIDOSIS-ALEXANDER,
ATKINS
disease at the age of 50 years. He had seven siblings, one of whom, a sister, also had kidney disease and high blood pressure. The patient was married and had 10 children who were all well. His only other complaint was polyuria, which had been present for several years. He had never had any edema or discoloration of his urine. On physical examination, he appeared ill. His complexion was sallow. The blood pressure was 240/120 mm Hg. Funduscopic examination revealed arteriolar tortuosity and some A-V nicking but no hemorrhages or exudates. He had a large palpable thyroid which was firm and nontender. There was no lymphadenopathy. His chest was clear, and the heart sounds were normal. No abdominal masses were felt. Laboratory investigations are presented in part in Table I. Urine specific gravity was 1.012, and several hyalin and coarsely granular casts were seen. Urine culture was negative. 17-ketosteroids were 10.2 mg/24 hours, and 17hydroxycorticosteroids were 8.5 mgJ24 hours. An immunoglobulin assay showed the immunoglobulin A (IgA) level to be 500 mg/lOO ml, immunoglobulin G (IgG) level 2,220 mg/lOO ml and the immunoglobulin M (IgM) level 64 mg/ 100 ml. Only the IgG level was considered to be elevated. Triiodothyronine level was 24.8 per cent. The plasma cortisol level was 16 pug/100 ml at 1000 hours and 12 pg/lOO ml at 2030 hours. A Mantoux test was positive at 1 in 10.000 dilution. Sputum cultures were negative for acidfast bacilli. No thyroid antibodies were isolated. The creatinine clearance was 17.5 ml/min. Electrocardiogram showed left ventricular hypertrophy. An intravenous pyelogram was interpreted as showing diminished concentration, but there was no abnormality on tomography of the kidneys. A bone marrow biopsy was carried out on December 13, 1968, and this was normal. A needle biopsy specimen of the thyroid, obtained on December 6, 1968, showed chronic thyroiditis. On November 29, 1968, needle biopsy of the right kidney revealed the presence of amyloid. The hypertension was controlled with methyldopa, 500 mg daily, and hydrochlorothiazide, 50 mg daily. The patient was readmitted to the Foothills Hospital in January 1970, with increasing fatigue, weakness, shortness of breath and generalized pruritus. Physical findings were as on the first admission except for a fall in blood pressure which was 1901105 mm Hg. The hemoglobin level was 8.8 g/100 ml, and the blood urea nitrogen level had risen to 89 mg/lOO ml with a serum creatinine level of 6.2 mg/lOO ml. The serum complement level was normal. Creatinine clearance was 14 ml/min. The protein content of a 24 hour urine collection was 4.6 g. An x-ray film of the chest showed fine nodular densities in both lungs, particularly in the upper lobes which had changed little since the previous admission. Gingival and rectal biopsies did not reveal any amyloid. The patient was readmitted to the Foothills Hospital on April 22, 197 1; he died 5 days later. His hemoglobin level was 6.0 g/ 100 ml, serum creatinine 18.0 g/100 ml and blood urea nitrogen 192 mg/lOO ml.
122
July 1975
The American Journalof Medicine Volume 59
Pathologic Findings Histologic examination of the biopsy specimen of the right kidney showed almost complete replacement of all the glomeruli by amyloid. There was extensive obliteration of the capillary lumens and a reduction in glomerular cellularity. The presence of amyloid was confirmed by methyl violet, Congo red and thioflavine-T stains. Associated with this loss of glomeruli, there was marked tubular atrophy and a moderate increase in interstitial fibrous tissue. No significant interstitial inflammation was present. Amyloid was not found in vessels, tubular basement membranes or interstitial tissue. Many of the tubules contained proteinaceous casts. Postmortem external examination revealed only an enlarged thyroid and edema of the feet and ankles. There were 150 ml of straw-colored fluid in each pleural cavity and some firm fibrous adhesions between visceral and parietal pleura over the upper lobes. In the lungs there were several firm to hard anthracotic nodules. The heart weighed 500 g and showed left ventricular hypertrophy. The liver weighed 1,340 g and was not firm or markedly congested. The spleen weighed 300 g. It was dark brown in color and of slightly firm consistency. Subcapsularly, a paler area was present. The right kidney weighed 130 g, the left 135 g. Both were firm, and the cortices appeared pale and waxy. No other lesion was found except for diverticulosis in the pelvic colon. The thyroid was pale, firm and nodular. Histologic examination confirmed the presence of a few silica-anthracotic nodules in the lungs. The thyroid contained a considerable quantity of fibrous tissue and a heavy lymphoid infiltrate without germinal centers. The main findings were deposition of amyloid confined to the kidneys, adrenals and spleen. No amyloid could be detected in any other tissue including liver, intestine, lymph node, peripheral nerve, subcutaneous tissue, heart and tongue. In the kidneys, the amyloid was as previously described in the biopsy specimen, but a few irregularly defined deposits of amyloid were also present in the medullary interstitial tissue. Blood vessels were not obviously involved in the cortex and could not be identified in the medullary nodules. In the adrenal glands, the amyloid was in the region of the zona reticularis mainly. The amyloid in the spleen did not involve the Malpighian bodies but formed a thick irregular layer on the inner aspect of the capsule. Many of the trabeculas were converted to thick bands of amyloid. Hemosiderin pigment was prominent in the splenic sinusoids. Special stains confirmed the presence of amyloid as described with no staining in other organs. Electron microscopy showed the typical fibrillar structure of the amyloid in the kidney. Case 2. A 54 year old man (A.S.) (brother of V.S., Case 1) was admitted to the Foothills Hospital on May 11, 1969, for investigation of proteinuria and hypertension. The proteinuria had been noted 3 years earlier, and for the past year there had been some swelling of his hands and feet. His only complaint was nocturia twice nightly. A few months prior to admission, he had been given Aldomet@, 500 mg daily, for hypertension. The patient had been born
FAMILIAL
in a small town in Southern Alberta, was single and worked as a ranch hand. The findings on physical examination were unremarkable except for slight pallor. Two linear hemorrhages were seen in the right fundus, but there was no other retinopathy. The blood pressure was 220/l 10 mm Hg. The liver was barely palpable. A sigmoidoscopic examination was within normal limits. Laboratory investigations are presented in part in Table I. Bence Jones protein was not found. Urinary steroid values were normal. An electrocardiogram showed left ventricular hypertrophy. A renal biopsy was carried out on May 15, 1969. The patient was discharged on antihypertensive medication; it was later learned that he died of renal failure in another hospital in February 1970. Gingival and rectal biopsies had been performed, but an autopsy had not been carried out.
Pathologic Findings No histologic abnormality was detected in the rectal or gingival biopsy specimens. Amyloid stains were negative. The kidney biopsy specimen showed cortex and medulla. The glomeruli were largely replaced by nodular and diffuse areas of amyloid deposition. Some tubular atrophy was observed but no amyloid was detected with special stains in vessels outside the glomeruli, tubules or interstitial tissue. Case 3. This 48 year old woman (M.L.) (a sister of VS., Case 1) first became ill in 1967 with the sudden onset of edema of her legs. She also had headaches, general malaise and nausea and was treated with antihypertensive medication. Proteinuria was detected initially in 1960 during her pregnancy. She had been married on two occasions. There were four children from her first marriage and one from the second marriage. Physical examination revealed a blood pressure of 160/ 100 mm fig. Her fundi showed only grade I retinopathy with mild arteriolar narrowing and no hemorrhages or exudates. The liver and spleen were not palpable, and there was no peripheral edema. The patient was admitted to the Foothills Hospital in January 1969 for further investigation of proteinuria, hypertension and renal insufficiency. The protein content of a 24 hour urine collection was 6.5 g. The serum creatinine was 4.0 mgf 100 ml with a blood urea nitrogen of 50 mg/ 100 ml. The serum proteins were 5.5 g/100 ml with a slightly abnormal electrophoretic pattern showing a small unidentified band between the beta and gamma globulin. Urine steroid levels were normal. Creatinine clearance was 12 ml/min. Renal and rectal biopsies were carried out. It was learned later that this patient died in another hospital of renal failure. An autopsy was not obtained. Pathologic Findings The glomeruli in the kidney biopsy specimen were almost completely replaced by homogeneous hyaline material staining positively for amyloid with methyl violet, Congo red and thioflavine-T. The tubules were mildly atrophic in
RENAL AMYLOIDOSIS-ALEXANDER.
ATKINS
areas, whereas a few were dilatea and contained proteinaceous casts. A few small focal accumulations of amyloid were identified in the interstitial tissue. No amyloid could be identified in blood vessels. The rectal biopsy specimen was negative for amyloid. Case 4. This patient (A.B.) (a maternal aunt of V.S., Case 1) died in 1964 at the age of 53. The final diagnosis was “chronic nephritis” with hypertension, edema and proteinuria. No autopsy was performed. She had first become ill early in 1953 at the age of 42 and was admitted to the hospital with proteinuria, urinary frequency, listlessness and tiredness. In April 1953, she was readmitted with “albuminuria,” and edema of the feet, ankles and eyelids. Blood pressure was recorded as 169/ 95 mm Hg. In 1959, she underwent a hemorrhoidectomy, and a diagnosis of “chronic nephritis” was also made at that time. Her blood pressure was recorded as high as 204/122 mm Hg. In June 1961, she reentered the hospital with “kidney trouble,” edema of her legs and headache. She had been taking diuretics for the previous 7 years. Blood pressure was 180/ 110 mm Hg and blood urea nitrogen 75 mg/ 100 ml. The patient’s final admission was in February 1964. Her chief complaints were weakness, dyspnea and ankle edema. She was pale with pitting edema to her knees. The optic fundi had arteriolar tortuosity and old hemorrhages were present. A diagnosis of uremia and chronic nephritis with secondary hypertension was made. The hemoglobin level was 5.6 g/l 00 ml, blood urea nitrogen 108 mg/ 100 ml, proteinuria 3-t, total carbon dioxide 44 meq/liter and blood pressure 180/l 10 mm Hg. Despite the administration of blood transfusions and diuretics, she became increasingly uremic, confused and dyspneic and died on March 29, 1964. Case 5. This patient (A.S.M.) (the mother of V.S., Case 1) died in St. Vincent’s Hospital, Pincher Creek, Alberta, on September 4, 1938, at the age of 46. No autopsy was performed, and the hospital records at that time were very sketchy. However, the physician’s comment was that she had suffered from “Bright’s disease” for 2 years, had high blood pressure and albuminuria. Her initial complaints were headache,’ weakness and dyspnea. She was born in Poland and came to Canada at an early age. She had been married twice and had 10 children, 6 from the first marriage and 4 from the second. Her parents apparently lived to be elderly, and there was no previous history of kidney disease in the family. COMMENTS Amyloid disease is recognized as occurring in primary and secondary forms. The latter is generalized in distribution and found in association with persistent chronic inflammation. The primary form may be generalized or involve a single organ-isolated organ amyloidosis. It may occur as sporadic cases or in a hereditary form. The best known examples of hereditary amyloidosis are Portuguese amyloid neuropathy
July 1975
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FAMILIAL RENAL AMYLOIDOSIS-ALEXANDER.
TABLE
I
Clinical and Laboratory Data
ATKINS
Findings on Admission
Case 1
Sex Blood pressure (mm Hg) Hemogloblin (g/100 ml) Edema Serum proteins (g/100 ml) Serum albumin (g/100 ml) Urinary protein/24 hours Serum immunoglobulins Serum creatinine (mg/lOO Blood urea nitrogen (mg/IOO ml) Liver function tests Serum cholesterol
Case 2
Case 3
M 210/120 11.6
M 220/110 9.7
F 160/100
+ 7.6 2.9 5.1
+ 4.3 1.8 9.2 Normal
+ 5.5 2.6 6.5 ...
f fgG
ml)
4.8
9.5
3.4
60
3.8
54
44
Normal 170
Normal 337
Normal 260
Yes
Yes
Yes
+ -
+
-
...
Absent
Absent
(m&100 ml) Death from renal failure Amyloid on renal biopsy Amyloid on rectal biopsy
+ -atau-
Amyloid
-at
on gingival
biopsy
topsy Absent
Fever, neuropathy, skin eruption, abdominal pain, eye lesions NOTE:
+ = positive;
-
=
topsy au-
negative.
[4] and familial Mediterranean fever [3], the former being a predominantly neuropathic form and the latter predominantly non-neuropathic. The familial nature of the disorder we describe is indicated by the similarity in the clinical and laboratory findings in the three siblings (Tables I and II). All three presented with proteinuria more than 5 g/24 hours, hypoproteinemia and edema, i.e., a nephrotic presentation. Renal biopsy in each case demonstrated amyloid which was almost exclusively observed within glomeruli. Hypertension was noted and all three siblings died from renal failure, as did their mother and a maternal aunt. The onset, or more accurately, the age of presentation, was in the 5th or 6th decade in each case, and the age at death ranged from 46 to 60 years. The family tree is shown in Figure 1. The most striking features exhibited by these siblings were the renal amyloidosis and the prominence TABLE
Chronology
II
of the Renal Disease
1
2
3
4
5
Average
VS. 58
A.S. 52
M.L. 42
A.B. 42
A.S.M. 44
47.6
60 2
55 3
49 7
51 9
46 2
+
+
+
+
+
Case Case Case Case Case Data Patients initials Age at presentation (yr) Age at death (yr) Duration of illness Death from renal failure
j24
July 1975
(yr)
The American Journal of Medlclne
52.2 4.6
Volume 59
of clinical features related to kidney disease. Renal amyloidosis is common in so-called secondary amyloidosis, but no predisposing cause was found in these cases. There was no history of chronic infection or inflammatory disease and although the serum IgG level was elevated in Case 1, there was no plasmacytosis and no cause found at postmortem examination. Serum immunoglobulin levels were normal in Case 2. The finding of amyloid in the kidneys of patients with hereditary amyloidosis is common, even though the principal manifestations of the disorder are less frequently related to the renal involvement. In Portuguese amyloid neuropathy, the renal amyloid is usually in the medulla and clinically insignificant. Nephropathy was also present in all but one of the pathologically verified familial amyloidosis cases of Van Allen [lo], although it was variable in quantity and distribution. Large vessel involvement by amyloid resulted in renal atrophy, and in several cases there was little amyloid in the renal cortex. Uremia was the most common cause of death, and the nephrotic state did not occur. Meretoja and Teppo [ 1 l] reported marked glomerular amyloid deposits in their cases of familial amyloidosis with cranial neuropathy. In patients with familial Mediterranean fever, Heller et al. [3] described 47 of 141 patients as having clinical renal disease, and in those coming to autopsy, there were particularly striking glomerular amyloid deposits. Severe renal involvement was also observed in the heredo-familial amyloidosis cases of Muckle and Wells [6]. Proteinuria was described in semiquantitative terms only (“large quantities,” “massive”), and the patients were not described as nephrotic. Death was often considered to be due to renal failure. Ostertag [S] observed nephropathy with albuminuria and hematuria progressing to renal failure in a mother, three children and a grandchild. Amyloidosis was widespread in the two members examined at autopsy and involved the kidneys. Maxwell and Kimbell [7] reported amyloid in the kidneys of three brothers, and nephropathy was the principal manifestation of amyloidosis in a Swedish family with pathoanatomic findings identical to those of familial Mediterranean fever
t91. Mahloudji et al. [6] discussed hereditary amyloidosis in neuropathic, non-neuropathic and localized forms. He considered three types of hereditary neuropathic amyloidosis: Type I Andrade (Portuguese), type II Rukavina (Indiana) and type Ill Van Allen (Iowa). The basic difference in these three forms lies in the distribution of the neuropathy-feet, hands and feet, and hands, respectively. He described a large Maryland kindred with a condition similar to type II Rukavina amyloid neuropathy. A number of reports of amyloid neuropathy in Japan [ 12,131 document a
FAMILIAL
RENAL AMYLOIDOSIS-ALEXANDER,
ATKINS
I
Figure 1. Family pedigree.
disease which is very similar to type I Andrade (Portuguese). Meretoja [ 141 and Meretoja and Teppo [ 1 l] described a further variety of familial amyloidosis with cranial nerve involvement as the principal manifestation. They called this a third type of familial amyloidosis with polyneuropathy, but omitted the well recognized Van Allen (Iowa) type. It should therefore be considered type IV, if one wishes to type them in this way. Hereditary amyloidosis of predominantly non-neuropathic type was first described by Ostertag [6,15]. The features included renal failure, hypertension and hepatosplenomegaly with autosomal dominant inheritance. In 1961, Heller et al. [S] described amyloidosis in familial Mediterranean fever, which is characterized by recurrent bouts of fever, arthritis and abdominal pain. Amyloidosis has been described as the sole manifestation of familial Mediterranean fever [ 161, and the disease has been divided into two phenotypes. In phenotype 1 the classic features are observed whereas in phenotype 2, amyloidosis is observed as the first clinical manifestation or sole manifestation. A new heredo-familial syndrome of urticaria, deafness and amyloidosis was reported by Muckle and Wells [8]. This condition starts during adolescence with chills, malaise and transient attacks of urticaria. Progressive deafness and nephropathy due to amyloidosis develop. This is a rare disorder, the fourth recorded study being presented by Black [ 171
in 1969. Other rare forms of non-neuropathic hereditary amyloidosis include a Russian family with allergic troubles and renal failure [ 181, cardiac amyloidosis [ 191 and hereditary cerebral hemorrhage and amyloidosis of cerebral vessels [20]. Less well documented cases of probable familial amyloidosis include those of Maxwell and Kimbell [7] followed up in 1967 as recorded by Mahloudji et al. [6] and the family described by Bergman and Warmenius [9] in Sweden. Renal involvement was marked in both these families. Mahloudji et al. [5] include a family with cold hypersensitivity and amyloid in the thyroid of one patient. No other material has been studied for the presence of amyloid in this family. The same patient was reported to have pinnal calcification associated with cold hypersensitivity by McKusick and Goodman [21]. Localized forms of hereditary or familial amyloidosis include medullary carcinoma of thyroid and pheochromocytoma [22] and varieties of cutaneous amyloid [23-261. Lattice cornea1 dystrophy was considered to be a localized form [27], but renal biopsy showed amyloid in glomeruli [28]. From the foregoing discussion it is obvious that renal involvement is the most prominent finding in many types of non-neuropathic hereditary amyloidosis. We, therefore, propose a classification of hereditary amyloidosis into neuropathic, nephropathic, miscellaneous and localized (Table Ill).
July 1975
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125
TABLE
III
Classification
of Familial
Classification
Alternate
Amyloidosis
Names
Ethnic Origin
Type I (Andrade) Type II (Rukavina) Neuropathic
form
Principal Manifestation Lower extremity Upper extremity
Portuguese and Japanese Swiss and German (Indiana, Maryland) Scottish-English, Irish
Type III (Van Allen)
Mixed
neuropathy neuropathy
upper and lower extremity
neuropathy
(Iowa) Type IV Heller et al. [3] familial Mediterranean fever Muckle, Wells [8] Ostertag Nephropathic form
Cranial
Finnish Jews, Armenians, generally English
[6]
Fever, abdominal or chest neuropathy Urticaria, deafness
Arabs
German
[9]
Swedish
Vinogradova et al. [18] Alexander, Atkins (present study)
pain,
arthritis
Nephropathy, hypertension, hepatosplenomegaly Chills and fever in childhood; nephropathy Abdominal pain, fever in childhood; nephropathy Allergies, renal failure Nephrotic syndrome, hypertension, renal failure
?
Maxwell, Kimble (71 Bergman, Warmenius
neuropathy
Russian Polish
Familial amyloid heart disease [19] Hereditary cerebral hemorrhage with amyloidosis [20] Lattice cornea1 dystrophy
Miscellaneous
F'7281 Cutaneous amyloid 123-261 Medullary carcinoma of thyroid and pheochromocytoma 1221
Localized
TABLE
IV
Comparison
of Features
in Recorded
Ostertag [6J Presentation
Cases and Present
Maxwell,
CASE 1: Poststreptococcal nephritis (age 31); hepatosplenomegaly
Kimball
[71
Bergman, Warmenius
CASE 1: Chills and fever in childhood; pain in kidney region; chronic rhinitis
(age 33)
CASE 2: Diphtheria, proteinuria (age 22); nephritis, headache, hypertension, proteinuria and casts (age 24); hepatosplenomegaly
Study Alexander, Atkins (present study) ~~.~ _._ CASE 1: Hypertension; nephrotic syndrome
[9]
CASE 1: Frequent attacks of abdominal pain, fever and nausea; scarlet fever (age 5); persistent proteinuria
(age 58)
(age 22) CASE 2: Frequent attacks of abdominal pain, fever and nausea; scarlet fever (age 10); persistent proteinuria
CASE 2: Chills and fever in childhood; pain in kidney region CASE 3: Chills and fever in childhood; pain in kidney region
CASE 2: Nephrotic syndrome; hypertension (age 52) CASE 3: Nephrotic syndrome; hypertension (age 42)
(age 14)
(age 25) Age at death
Organs involved by amyloid Liver Spleen
CASE 1: 45 CASE 2: 43 CASE 3: 43
CASE 1: 35 CASE 2: 39
(yr)
CASE 1
CASE 2
CASE 1
CASE 2
CASE 3
CASE 1
CASE 2
+
+
...
+
+
(2 kg) +
...
+ +
+ +
+ +
+ (4.6 kg) +
Kidneys Adrenals Others NOTE: T.B. = caseous
+ + +
(6Tg)
(2.:kg)
(95Tg) + + +
(9Oig) + + ...
tuberculosis;
+ = present;
(2.3+kg)
... -
CASE 1: 35 CASE 2: 21
-
= absent;
+T.B.
+
. , . = unknown.
+
1::
CASE 1: 60 CASE 2: 55 CASE 3: 49
CASE 1 -
CASE 2
CASE 3
...
. .
(3OTg)
..’ +
‘.. +
_’
‘i
+ +
_
or
FAMILIAL RENAL AMYLOIOOSIS-ALEXANDER
Do the cases presented in this report represent a new variety of familial amyloidosis? There were no neuropathic symptoms and the nerves were not involved by amyloid at autopsy, so they would not fit into the group of hereditary amyloidosis of predominantly neuropathic type. The absence of (1) the clinical features of familial Mediterranean fever in these patients or their relatives, (2) urticaria and deafness, (3) allergies, (4) progressive cardiac failure, (5) cerebral hemorrhage and (6) cornea1 dystrophy exclude them from these six types. We are, therefore, left with the early cases of Cstertag [6,15], Maxwell and Kimble [7] and the more recent cases of Bergman and Warmenius [9] to consider. The important features are presented in Table IV. The presentation in the cases described by Bergman and Warmenius [9] is very similar to that in familial Mediterranean fever, and pathoanatomic findings are identical. These patients may represent a variety of this syndrome, despite their Swedish origin. Familial Mediterranean fever has been described in an Italian family [29] and in members of other ethnic groups around the Mediterranean (French [four], Spanish [three], Italian [three], Greek [two], Iranian [one]) and also from Sweden [four] and Holland [one] [30]). Th ey d’ff I er f rom this report in their clinical presentation and the generalized nature of the amyloidosis. The patients of Ostertag [6] differ from those we describe in their clinical presentation and distribution of amyloid. Noteworthy differences are the diagnosis of nephritis in both patients (although exactly what is meant by nephritis is uncertain), hepatosplenomegaly and massive involvement of the liver by amyloid. However, the relatively scanty information available on these patients makes a thorough comparison difficult.
ATKINS
The three brothers described by Maxwell and Kimbell [7] are similar in their predominantly renal symptoms to the siblings we describe, but attacks of chills and fever were also noted in childhood. A son of one of the brothers had the same childhood symptoms plus a skin rash and died of renal amyloidosis at age 39. Two of his children have had frequent bouts of fever with severe transient joint pains and maculopapular rashes. No deafness was observed in any members of this kinship. None of the three brothers had hypertension; all had amyloid in the liver and one of them had disseminated caseous tuberculosis. The distinctive features of the family reported here are the pure renal symptoms-an insidious onset of nephrotic syndrome and hypertension. No fevers, chills or rashes have been observed in any of their children. The distribution of amyloid is confined to the kidneys, spleen and adrenals. The distribution of the amyloid in the spleen with marked involvement of the capsule and subcapsular area is also unusual. The patients are of Polish extraction, an ethnic group in which we have been unable to find a report of familial amyloid nephropathy. We, therefore, believe that they justify inclusion as having a further variety of familial renal amyloidosis. Study of the following generation as they reach middle age will help to define this entity more clearly.
ACKNOWLEDGMENT We wish to thank Dr. D. J. Goddard and Dr. M. R. Hodgson of Pincher Creek, Alberta. Their cooperation and assistance in clinical follow-up was essential to the case studies of these patients. Thanks are also expressed to Dr. R. Lannigan, Professor and Head, Division of Pathology, The University of Calgary, for his helpful criticism and advice.
REFERENCES 1. Magnus-Levy A: Amyloklosis in multiple myeloma. Progress 2. 3. 4.
5.
6. 7.
noted in 50 years of personal observation. J Mount Sinai Hosp NY 19: 8, 1952. Osserman EF, Fahey JL: Amyloidosis and plasma cell dyscrasia. Am J Med 44: 256, 1958. Helfer H, Sohar E, Gafni J, Heller J: Amyloidosis in familial Mediterranean fever. Arch Intern Med 107: 539, 1961. Andrade C: A peculiar form of peripheral neuropathy. Familial atypical generalised amylokfosis with special involvement of peripheral nerves. Brain 75: 408, 1952. Mahloudji M, Teasdall RD, Adamklewicz JJ, Hartman WH, Lambird PA, &Ku&k VA: The genetic amyloidoses. Medicine 48: 1, 1969. Ostertag B: Demonstration einer eigenartigen familiaren “Paramyloidose.” Zentralbl Allg Pathol 56: 253, 1932. Maxwell ES, Kimball I: Familial amyloidosis with case reports. Med Bull VA 12: 365, 1936.
8. 9. 10.
11.
12. 13. 14.
July 1975
Muckle TJ. Wells M: Urticaria, deafness and amylokfosis. A new he&o-familial syndrome. Q J Med 31: 235. 1962. Bergman F. Warmenius S: Familial perireticular amyloidosis in a Swedish family. Am J Med 45: 601, 1988. Van Allen MW, Frohlich JA. Davis JR: Inherited predisposition to general&d amyloiosis. Clinical and pathological study of a family with neuropathy, nephropathy and peptic ulcer. Neurology 19: 10, 1969. Meretoja J, Teppo L: Histopathological findings of familial amyloklosis with cranial neuropathy as principal manifestation. Report of three cases. Acta Pathol Microbial Stand 79-A: 432. 1971. Nakagawa S, Suzue K: Amyloiiosis in Japan. Pathol Microbiol (Basel) 27: 850, 1964. Araki S, Mawatari S, Ohta M: Polyneuritic amyloidosis in a Japanese family. Arch Neural 18: 593, 1968. Meretoja J: Familial systemic paramyloidosis with lattice
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FAMILIAL RENAL AMYLOIOOSIS-ALEXANDER, ATKINS
15. 16.
17. 18. 19.
20.
21
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128
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