Hyaline Replacement Amyloid of Islets of Langerhans

Hyaline material/amyloid of the islets of Langerhans is also found in patients with endstage renal failure (ESRF) on dialysis treatment [8, 9] and in patients after gastrectomy [10, 11].

In Patients with Endstage Renal Failure on Dialysis Treatment

With the advent of periodic dialysis, patients with chronic renal failure can be maintained in relatively good health over long periods of time. It is well known that these patients often develop infectious disease, pathological fractures of the bone, renal neoplasm, disturbance of lipid metabolism and entrapment neuropathy, as complications.

It is known that patients with renal failure are unable to adequately handle a glucose load [12] and are unable to augment insulin secretion sufficiently to overcome peripheral antagonism to insulin [13]. In patients receiving dialysis therapy, abnormal glucose tolerance is observed.

According to Suda and Ariwa [8], hyaline replacement of the islets of Langerhans is found in 6 ESRF patients who have received chronic dialysis for more than 2 years and 10 months (fig. 1), as shown in table 1. The percentage of

Table 1. Histopathologic findings of the islets of Langerhans in patients with endstage renal failure (ESRF) on dialysis treatment (10 cases) (8)

Case

Age

Sex

Clinical

Periods of

Islets of

Blood

Urine

no.

years

diagnosis

hemodialysis

Langerhans*

glucose level mg/dl

glucose level

1

72

F

chronic nephritis

1 year, 1 month

degenerative

164

<0.25 g/dl

2

45

M

chronic nephritis

1 year, 6 months

degenerative

3

70

F

chronic renal failure

2 years

4

51

F

SLE

2 years, 2 months

160

5

36

F

chronic nephritis

2 years, 10 months

hyaline replaced (44.2)

435

6

62

M

gout

3 years, 4 months

hyaline replaced (3.4)

negative (2 years ago)

7

49

M

ESRF

5 years

hyaline replaced (14.6)

negative (5 years ago)

8

58

F

chronic nephritis

7 years

hyaline replaced (8.3)

(6 years ago) positive (2 years ago)

9

73

M

chronic nephritis

7 years

hyaline replaced (42.1)

186

10

62

M

chronic nephritis, liver cirrhosis and hepatocellular carcinoma

10 years, 10 months

hyaline-replaced (11.4)

95

*Figures in parentheses represent the percentage of involved islets.

*Figures in parentheses represent the percentage of involved islets.

islets of Langerhans involved by hyalinosis ranged between 3.4 and 44.2%. Clinically, although urine glucose is only positive in 1 of 6 patients with hyaline islets, the blood glucose level is moderately elevated in 2 other cases, and that finding is related to the hyaline replacement of the islets of Langerhans.

The hyaline-replaced islets were stained positively with Congo red and showed green fluorescence under polarized light. Electron microscopy revealed a fine fibrillar structure, 10-12 |xm wide, with nonbranching fibrils running in different directions. Hyaline replacement of the islets of Langerhans stained positive for anti-amyline (or islet amyloid polypeptide).

The hyaline replacement of islets of Langerhans in patients with ESRF receiving chronic dialysis seems to be resulting from dialysis therapy. Avram [14] has an explanation for pancreatic abnormality in patients receiving dialysis therapy. Three reasons seem to be related to the change in the islets: (1) Based on thickened arterioles in the pancreas as part of systolic blood vessel disease; (2) repeated volume contraction occurs during maintenance dialysis. In cases using a glucose-containing dialysate, there will usually be a net gain of glucose during dialysis, depending upon the relative glucose concentrations in serum and dialysate [15]; (3) with increased patient survival, islet changes may be a manifestation of the natural progression of ESRF. According to de Koning et al. [9], amyloid deposits were found in 8 of 23 non-diabetic patients with ESRF (35%) on chronic dialysis treatment, which was higher than the prevalence in non-diabetic control subjects (3%) (p < 0.01). There was no relationship was found between the duration of dialysis treatment and the presence of islet amyloid deposits derived from insulin amyloid polypeptide (IAPP), a 37-amino-acid peptide, which is the main proteinaceous component of islet amyloid and is localized in B cell secretory granules [16, 17]. This suggests that long-term exposure to high plasma concentrations of IAPP is not the only factor for islet amyloidosis in patients with ESRF: insulin resistance, the associated B cell hypersecretion of insulin and IAPP are likely to play a more important role in amyloid deposition. Several authors [18, 19] report a high prevalence of amyloid deposition in osteoarticular tissues in patients with ESRF on chronic dialysis treatment. Patients with ESRF on dialysis treatment also have increased concentrations (up to 20 times) of the amyloidogenic protein beta 2-microglobulin [20], which are the major constituent fibrils in dialysis-related amyloidosis. However, plasma concentrations of IAPP have been shown to be elevated in patients with ESRF compared with subjects without renal disease [21, 22]. Impaired renal clearance is an important determining factor for high concentrations of circulating IAPP found in patients with end-stage renal disease.

Therefore, the hyalinosis of the islets of Langerhans seems to be either a complication of dialysis itself or probably the result of long-term endstage renal failure.

In Patients after Gastrectomy

After gastrectomy, patients often experience such complications as the dumping syndrome, gallstones, and malabsorption. These patients cannot adequately process a glucose load [23]; indeed, gastric surgery is a well-recognized cause of impaired glucose tolerance [24]. Alterations in glucose metabolism after partial gastrectomy, with a rapid increase and high peak concentration of glucose, are due in large measure to an increased rate of gastric emptying and, consequently, to an increased rate of intestinal absorption [25].

According to Suda et al. [10], in all but two patients in the Billroth (B) groups shown in tables 2 and 3, fewer than 10% of the islets show hyalinization (fig. 2). Such a small reduction in the percentage of functioning islets may seem to bear no relation to the significant impairment of insulin production. However,

Case

Age years

Sex

Periods after gastrectomy

Islets of Langerhans*

Blood glucose level mg/dl

1

88

M

2 years, 6 months

Hyaline replaced (0.9%)

115

2

74

F

10 years

NA

72-121

3

78

M

10 years

Hyaline replaced (1.2%)

122-279

4

81

F

12 years

Hyaline replaced (1.2%)

139

5

87

M

12 years

Hyaline replaced (2.2%)

95-123

6

79

M

15 years

NA

88-106

7

58

M

15 years

Hyaline replaced (0.5%)

83-143

8

54

M

15 years

Hyaline replaced (2%)

62

9

77

M

18 years

NA

-

10

78

M

19 years

Hyaline replaced (5.7%)

102

11

87

M

20 years

Hyaline replaced (6.8%)

-

12

77

F

20 years

NA

-

13

81

F

24 years

NA

98

14

85

M

28 years

NA

103-160

15

69

M

34 years

Hyaline replaced (14.3%)

160

*Figures in parenthesis represent the percentage of involved islets. NA = Not applicable.

*Figures in parenthesis represent the percentage of involved islets. NA = Not applicable.

blood glucose levels were mildly elevated in three patients with B-I who showed hyalinization in the islets of Langerhans, and one patient with B-II showed an elevated glucose level. Thus such a small reduction in the percentage of functioning islets may reflect mild, but not significant, impairment of insulin production.

Although reasons for the occurrence of hyaline replacement of the islets of Langerhans in these persons after gastrectomy remain obscure and data on carbohydrate metabolism in these persons remain scanty, hyalinization in the islets of Langerhans is obvious [10, 11].

In animals, the vagus nerve is involved in insulin secretion [26, 27]; because vagotomy is performed in most gastric operations, this may contribute to postprandial hyperglycemia. Vagotomy may alter the release of gastrointestinal peptides from the mucosa of the small intestine, which, in turn, affects absorption and glucose tolerance [24].

After total or partial gastrectomy, dumping syndrome followed by secondary hypoglycemia may occur. Early dumping syndrome is due to the rapid passage of ingested food, which causes distension of the jejunum. The rapid absorption of carbohydrate produces marked hyperglycemia, an excessive stimulus [28] that causes the islets to became hyperactive, and this, finally, results in their hyalinization.

Case Age years Sex Period after gastrectomy Islets of Langerhans* Blood glucose level mg/dl

1

77

M

3 years, 8 months

Hyaline replaced (11.6%)

100

2

63

M

8 years, 6 months

Hyaline replaced (0.2%)

-

3

84

M

10 years

NA

-

4

71

F

16 years

NA

-

5

61

M

18 years

NA

87-99

6

76

M

20 years

Hyaline replaced (6.3%)

-

7

52

M

21 years

Hyaline replaced (1%)

102

8

71

M

21 years

Hyaline replaced (0.8%)

90

9

83

F

25 years

Hyaline replaced (2.5%)

131-182

10

56

M

26 years

NA

89

11

69

M

29 years

NA

-

12

58

M

29 years

Hyaline replaced (7.1%)

112

13

80

M

30 years

Hyaline replaced (3.6%)

-

14

54

M

30 years

NA

-

15

61

M

30 years

NA

144

16

78

F

40 years

NA

-

*Figures in parenthesis represent the percentage of involved islets. NA = Not applicable.

*Figures in parenthesis represent the percentage of involved islets. NA = Not applicable.

Hence, hyperplasia of the islets of Langerhans and increased numbers of endocrine cells were seen during the early period after gastrectomy. In contrast, the islets of Langerhans showed atrophy and decreased numbers of endocrine cells more than 5 years after gastrectomy. These changes suggested that B cells in the islets of Langerhans subsequently became wasted and atrophic after hypersecretion of insulin [11].

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