FIGURE 2 - uploaded by Intissar Anan
Content may be subject to copyright.
Cell number, CSI, and nuclear area of different endocrine cell types in antrum of stomach. Box and Whisker presentation of median, 25th to 75th percentiles, and ranges. denote FAP before transplantation; o FAP after transplantation ; f controls. *P<0.05, **P<0.01.
Source publication
The aim of this study was to investigate familial amyloidotic polyneuropathy, Portuguese type patients' endocrine cell content in the stomach and duodenum before and after liver transplantation, and to relate the findings to the patients' gastrointestinal disturbances.
Ten liver-transplanted familial amyloidotic polyneuropathy, Portuguese type pati...
Citations
... The intestinal endocrine cells have been investigated in the small and large intestine, and profound depletion was noted [24][25][26]. However, after liver transplantation, the number of endocrine cells returned to normal levels, without a corresponding normalisation of the GI symptoms; thus, the role of endocrine GI cells is uncertain [27]. A recent investigation of the intestinal cells of Cajal in the gastric ventricle noted a marked depletion [28]. ...
Purpose
To review the management of gastrointestinal symptoms in patients with hereditary transthyretin amyloidosis, discussing diagnostic evaluations, assessment of disease progression and therapeutic strategies that could be implemented in routine practice.
Methods
Literature review. Key search terms included “gastrointestinal symptoms”, “autonomic neuropathy”, “hereditary transthyretin amyloidosis” and “familial amyloid polyneuropathy”.
Results
Gastrointestinal disturbances are a common and serious manifestation of hereditary transthyretin amyloidosis, with significant effects on patients' quality of life and demonstrating a strong association with mortality. Gastrointestinal involvement is more often subclinical in the early stages of the disease, although in some patients gastric and/or bowel abnormalities may be the inaugural symptoms. In both cases, under-recognition, delayed investigation and suboptimal treatment frequently occur. A clear understanding of the mechanisms underlying gastrointestinal dysfunction in hereditary transthyretin amyloidosis is still lacking, but similar to diabetic enteropathy, multiple pathophysiological alterations seem to play a role.
Conclusions
Early detection and treatment of gastrointestinal disturbances is key to the successful treatment of this devastating disease. Gastroenterologists play a valuable role in both the diagnosis and the timely management of gastrointestinal symptoms in hereditary transthyretin amyloidosis and should, therefore, be part of a multidisciplinary and comprehensive approach to this disorder.
... Successful liver transplantation in ATTRm amyloidosis patients is generally accompanied by a stabilization of GI symptoms, and although an improvement cannot be expected, an increase in mBMI and recovery of symptoms have been noted in some studies [28,42]. We have found a normalization of neuroendocrine intestinal cells after liver transplantation, although this was also not accompanied by an improved GI function [53]. No improvements of autonomic nervous function or gastric emptying were found after transplantation, and the GI symptoms even tended to increase in another of our studies [21]. ...
Introduction: Hereditary transthyretin amyloidosis (ATTRm amyloidosis) is a rare disease caused by the deposition and accumulation of insoluble non-native transthyretin fibrils in the body. The disease inevitably results in widespread organ disruption, and poor life expectancy. The GI tract is one organ system vulnerable to disruption and, although the clinical presentation of the disease varies, GI involvement affects most patients with ATTRm amyloidosis.
Areas covered: This article presents our experience with diagnosing and treating the GI symptoms of ATTRm amyloidosis patients at our center over the last 40 years, in the Swedish clustering area of the disease. Our aim is to help other physicians to better manage GI complications in patients with this rare but widespread condition.
Expert commentary: GI symptoms are debilitating complications for ATTRm amyloidosis patients to experience, yet with the appropriate questioning and diagnosis methods, symptomatic treatments of these symptoms can be implemented to provide relief. Further, patients with fewer GI complications and a good nutritional status are also better candidates for liver transplantation which, in selected cases, is the best disease-modifying treatment of ATTRm amyloidosis to date.
... Both factors of the mBMI composite endpoint (BMI and serum albumin level) are expected to be negatively impacted by the late-stage disease often associated with malabsorption. Although depletion of neuroendocrine cells along the gastrointestinal tract from the stomach to the colon was hypothesized to engender gastrointestinal disturbances[27][28][29], no improvement of gastrointestinal function was found after liver transplant[30][31][32], even when the endocrine cell count in the upper part of the tract normalized[30]. Attention has turned to the loss of interstitial pacemaker cells gastric wall of 11 deceased Japanese patients with Val30Met TTR-FAP and attendant gastrointestinal complications, compared with 10 deceased non-TTR-FAP patients[33]. ...
... Both factors of the mBMI composite endpoint (BMI and serum albumin level) are expected to be negatively impacted by the late-stage disease often associated with malabsorption. Although depletion of neuroendocrine cells along the gastrointestinal tract from the stomach to the colon was hypothesized to engender gastrointestinal disturbances[27][28][29], no improvement of gastrointestinal function was found after liver transplant[30][31][32], even when the endocrine cell count in the upper part of the tract normalized[30]. Attention has turned to the loss of interstitial pacemaker cells gastric wall of 11 deceased Japanese patients with Val30Met TTR-FAP and attendant gastrointestinal complications, compared with 10 deceased non-TTR-FAP patients[33]. Interestingly, similarities between the gastroenteropathies associated with TTR-FAP and type 2 diabetes mellitus may be relevant. ...
Gastrointestinal symptoms are common among patients with transthyretin familial amyloid polyneuropathy (TTR-FAP). This post hoc analysis evaluated the nutritional status of TTR-FAP patients treated with tafamidis while enrolled in clinical trials.
Nutritional status was measured by the modified body mass index (mBMI = BMI × albumin level). Treatment-related changes in mBMI were reported for 71 Val30Met TTR-FAP patients who completed an 18-month, randomized, double-blind, placebo-controlled trial and who continued into its open-label, 12-month extension.
At month 18, mBMI worsened in the placebo group (n = 33) (-33 ± 16 kg/m(2) g/l, P = 0.04 versus baseline) but improved in the tafamidis group (n = 38) (+37 ± 14 kg/m(2) g/l, P = 0.01 versus baseline) such that the effect size between the groups was statistically significant (P = 0.001). By month 30 (completion of the open-label extension), placebo patients with 12 months of tafamidis treatment and tafamidis-treated patients with 30 months of treatment both tended to increase their mBMI (28 ± 19 kg/m(2) g/l and 16 ± 18 kg/m(2) g/l, respectively). Increase in BMI was most pronounced in patients with low BMI at entry into the studies.
mBMI is well suited to monitor disease progression in TTR-FAP patients. The delay in neurological deterioration brought about by tafamidis treatment in clinical trials is associated with improvements in, or maintenance of, mBMI.
This study was sponsored by Pfizer Inc., New York, USA.
... However, as mentioned above, some studies show that the enteric nervous system is not affected in ATTR V30M patients and there was only a weak correlation between the autonomic function and the gastric emptying rates in another of our studies [23]. Moreover, the GI function is not improved after liver transplantation [24,25], although a normalization of the endocrine cell count can be observed [26]. An autonomic dysfunction is indeed important for some of the complications in patients with hereditary TTR amyloidosis, but it remains unclear to what extent the autonomic and enteric neuropathies affect their gastrointestinal function. ...
Background
Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls.
Methods
Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee.
Results
The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively).
Conclusions
A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.
... [22][23][24][25] However, the enteric nervous system seems to be unaffected in FAP Val30Met 26,27 and no improvement of the GI function has been shown after Ltx, 28,29 although a normalization of the endocrine cell count was noted. 30 In diabetes mellitus a down-regulation of ghrelin and its receptor is linked to GI dysfunction, 31,32 and it would be of interest to study if this is also the case in FAP patients. ...
Background
Gastrointestinal (GI) complications are common in hereditary transthyretin amyloidosis and an autonomic dysfunction has been considered to explain these symptoms. The aim of this study was to investigate the impact of autonomic neuropathy on gastric emptying in hereditary transthyretin amyloidosis and to relate these findings to nutritional status, GI symptoms, gender, and age at disease onset.
Methods
Gastric emptying was evaluated with gastric emptying scintigraphy. Spectral analysis of the heart rate variability and cardiovascular responses after tilt test were used to assess the autonomic function. The nutritional status was evaluated with the modified body mass index (s-albumine × BMI).
Key Results
Gastric retention was found in about one-third of the patients. A weak correlation was found between the scintigraphic gastric emptying rate and both the sympathetic (rs = −0.397, P < 0.001) and parasympathetic function (rs = −0.282, P = 0.002). The gastric emptying rate was slower in those with lower or both upper and lower GI symptoms compared with those without symptoms (median T50 123 vs 113 min, P = 0.042 and 192 vs 113 min, P = 0.003, respectively). Multiple logistic regression analysis showed that age of onset (OR 0.10, CI 0.02–0.52) and sympathetic dysfunction (OR 0.23, CI 0.10–0.51), but not gender (OR 0.76, CI 0.31–1.84) and parasympathetic dysfunction (OR 1.81, CI 0.72–4.56), contributed to gastric retention.
Conclusions and Inferences
Gastric retention is common in hereditary transthyretin amyloidosis early after onset. Autonomic neuropathy only weakly correlates with gastric retention and therefore additional factors must be involved.
... However, as mentioned above, some studies show that the enteric nervous system is not affected in ATTR V30M patients and there was only a weak correlation between the autonomic function and the gastric emptying rates in another of our studies [23]. Moreover, the GI function is not improved after liver transplantation [24,25], although a normalization of the endocrine cell count can be observed [26]. An autonomic dysfunction is indeed important for some of the complications in patients with hereditary TTR amyloidosis, but it remains unclear to what extent the autonomic and enteric neuropathies affect their gastrointestinal function. ...
... Few studies of gastrointestinal function after transplantation have emerged. We found a normalisation of enteric neuroendocrine cell depletion after transplantation, but it was not associated with any symptomatic improvement (Anan et al. 2000). Even though nutritional status and symptoms for many patients have improved after transplantation, objective measurements have shown a stabilisation of the patients' gastrointestinal function, and generally no improvement (Lang et al. 2000;Suhr et al. 2003). ...
Liver transplantation has until now proved to be the only treatment available that halts the progression of hereditary transthyretin (TTR) associated amyloidosis. The rationale behind the procedure is to replace the liver producing variant TTR with one that produces wild type TTR only, and thereby cease the production of amyloidogenic TTR (ATTR). Even though the transplantation does not improve the patient's symptoms, the progression of the disease comes to a halt for a majority of patients. However, unforeseen complications after the transplantation have emerged, in particular a continuous amyloid formation in the heart observed in non-ATTR Val30Met mutations. Thus, combined liver and heart transplantation has been performed in selected cases.
Since the ATTR liver functions normally apart from a synthesis of the variant TTR, utilisation of ATTR-amyloid patients' livers for transplantation of liver disease patients has been performed. In a few patients, development of amyloid disease has been reported, but the procedure remains an important source of organs, especially for patients with hepatocellular cancer.
... Although the status of the patients seems unchanged after transplantation concerning amyloid deposits (54,(56)(57)(58)(59), ocular manifestations appear after LTx (60), caused by a local production of TTR in the eye. Moreover, a progression of cardiomyopathy was found in FAP patients with the ATTR Val30Met mutation when they were examined 4 to 6 years after LTx, noted as increased left ventricular wall thickness and left atrial dimension (61). ...
... Abdominal fat samples were examined for TTR amyloid by Congo red staining and immunostaining for TTR and anti-lambda light chain by the avidinbiotin complex (ABC) method (DAKO A/S, Glostrup, Denmark) [5]. The primary antiserum was raised in rabbit against TTR (dilution 1:400, code No. A0002, DAKO A/S, Denmark) and lambda light chain. ...
We report two new amyloidogenic transthyretin (TTR) variants detected in the Swedish population. One variant was previously unknown, while the other has been described in a French family. In Swedish patients, both variants have caused late-onset cardiac amyloidosis characterised by heart failure. In both cases, the diagnosis was determined by the detection of amyloid deposits in skin and/or rectal biopsies and identification of TTR mutations by genetic analysis. The index case of the previously unknown mutation (ATTR His88Arg) was a 66-year-old Swedish man, who sought medical attention for increasing dyspnea. Echocardiographic examination disclosed a restrictive cardiomyopathy, and subsequent examinations disclosed TTR amyloidosis. The patient is alive with moderate symptoms one year after the onset of disease. The index case for the new Swedish mutation (ATTR Gly53Glu) is a woman who sought medical attention at the age of 57 because of increasing dyspnea. Echocardiographic examination disclosed a hypertrophic cardiomyopathy with diastolic impairment. The diagnosis of systemic amyloidosis was made by fat aspiration biopsy and histopathology. The patient developed severe intractable heart failure, with pulmonary effusion and ascites. She died four years after the onset of her disease of intractable heart and kidney failure. Post mortem examination of biopsy specimens and blood revealed TTR amyloid deposits and the ATTR Gly53Glu mutation was detected.
... Some improvements have been reported, but generally the patients status has been unchanged after transplantation related to amyloid deposits (7,9,10). A study based on whole-body serum amyloid protein scintigraphy showed a decrease of amyloid deposits in 5 of 10 (50%) patients after OLT (11), and in intestinal biopsy material, no progression of amyloid deposits after OLT was observed (12). ...
Orthotopic liver transplantation (OLT) is today the only available treatment to halt the progress of familial amyloidotic polyneuropathy (FAP). Because heart arrhythmia and conduction disturbances are well-known manifestations of FAP, the aim of this study was to investigate the occurrence and development of heart conduction and rhythm disturbances in Swedish FAP patients who underwent liver transplantation.
Ambulatory 24-hour electrocardiography (ECG) recordings (Holter-ECGs) were available from 30 patients, who had been investigated before and reexamined after OLT. RESULTS.: The number of patients with abnormalities on their ECG recordings increased after OLT. Four patients developed serious arrhythmia after transplantation that necessitated the insertion of a pacemaker 40 months or longer after OLT.
The development of cardiac conduction disturbances and arrhythmias appear not to be halted by liver transplantation, indicating that the physician should be aware of the potential risk for FAP patients receiving transplants to develop fatal arrhythmia. The follow-up after liver transplantation should include Holter-ECG recordings.
