Review for 10.1186/1471-230X-13-71 (2013)

Reviewer's report
Title:Chronic Diarrhea as the Presenting Feature of Systemic Amyloidosis
Associated with Multiple Myeloma: a case report
Version: 1Date:12 March 2013
Reviewer: Marco Di Girolamo
Reviewer's report:
Review of a Case report
Title : Chronic Diarrhea as the presenting feature of systemic Amyloidosis
associated with multiple myeloma: a case report”
The case report submitted to BMC Gastroenterology fall under the category 2:
“unexpected or unusual presentations of a disease”
My comments are divided in two categories:
Discretionary Revisions
I suggest the author consider the following :
Aim of the case report
The manuscript could be interesting (point 2 of guidance for reviewers) only if it
would be stressed that the ambiguous onset of the disease can bring to a delay
of diagnosis, in spite of the presence of “red flag” of the disease that sometimes
are not investigated. Moreover, the case report is interestingly instructive: it offers
the opportunity to point out how sometimes a diagnosis is reached by using
some available data without recognizing that already by the time of the disease
onset were available other clinical findings
This phenomenon is instructive to encourage doctors to better evaluation of all
diagnostic elements as a whole (instrumental, laboratory, clinical and anamnestic
data)
For this reason I suggest to the authors that the title (and also the intention of the
communication) might be better as follows : “ Chronic diarrhea as the presenting
feature of systemic AL amyloidosis : a case report. Serendipity or delayed
diagnosis ? “
Etiology of Chronic diarrhea
It is necessary to study deply the differential diagnosis with the other conditions
of chronic diarrhea.
A definite cause of diarrhea illness is often not identified. Chronic diarrhea is
defined as diarrheal illness lasting for more than 4 weeks.
Much more emphasis is needed to the differential diagnosis above all for the
more frequent and rare causes of “secretory diarrhea” that are the more difficult
to diagnose. There are many causes of chronic diarrhea (chronic inflammatory ,
infections, ischemic colitis, malignancy, malabsorption and maldigestion
syndromes, chronic watery diarrhea (osmotic, secretory ).
The differential diagnosis of secretory diarrhea should includes infections,
structural diseases, endocrinopathy and peptide-secreting tumors (tireotossicosi,
VIPoma, carcinoide, gastrinoma,)
Pag 3
You describe: “ The past medical history was remarkable for a diagnosed
tuberculous pericarditis twenty years ago. No obvious abnormality was detected
by echocardiography after half a year treatment with standard anti-tuberculosis
regimen.
How many years ago was performed echocardiography ? Has never been
previously reported the appearance of hypertrophic cardiomyopathy ?
Diagnosis of primary AL amyloidosis or secondary to multiple myeloma
In the presentation is indicated that the patient showed a monoclonal
gammopathy without evidence of any osteolytic lesions of the X-ray controls and
11.5% of bone marrow plasma cells. This clinical condition is more characteristic
of a primary form of amyloidosi AL rather than a form of secondary amyloidosis
plasma-cell myeloma Associated.
For this reason I think it is more appropriate to amend the text when it comes to
"systemic amyloidosis associated with multiple myeloma" with the words "primary
systemic AL amyloidosis"
Moreover (pag.4)
The diagnosis of Amyloidosis must be confirmed by tissue typing fibril tissue
deposit by immunochemistry.
Many reasons confirm that: amyloid deposit in the gastrointestinal tract could be
present in the primary and secondary amyloidosis. The symptoms and findings
are nonspecific and resemble those of chronic inflammatory bowel disease and
ischemic colitis. Secondary amyloidosis can be seen as a rare complication of
Crohn's disease and ulcerative colitis. Special staining is necessary to show
amyloid deposit, and the distinction between primary and secondary amyloidosis
requires immuno-histochemistry. Only with such a method it is possible to avoid
the risk (rare but significant) to give to a patient the therapy wrongly considering
him affected by amyloidosis AL (of hemathologic origin), whereas it is
amyloidosis AA (secondary for example of a chronic flogistic disease of the
bowel) or, more rarely amyloidosi TTR (due to a mutation of the transthyretin
gene).
[About this diagnostic problem it is shown below a useful reference
"http://www.nejm.org/doi/full/10.1056/NEJMoa013354"
Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis
June 6, 2002 Lachmann H.J., Booth D.R., Booth S.E., et al. N Engl J Med 2002;
346:1786-1791
Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes
encoding transthyretin, fibrinogen A
Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes
encoding transthyretin, fibrinogen A #-chain, lysozyme, or apolipoprotein A-I, is
thought to be extremely rare and is not routinely included in the differential
diagnosis of systemic amyloidosis unless there is a family history.
Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent),
most often in the genes encoding fibrinogen A #-chain (18 patients) and
transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary
amyloidosis was confirmed by additional investigations. A low-grade monoclonal
gammopathy was detected in 8 of the 34 patients (24 percent).
Pag. 5 The diagnostic delay
Well talk about the diagnostic delay, but be careful about "rarity" of the
presentation, especially if (in the case report describe that there were other
diagnostic elements (hypertrophic heart disease, orthostatic hypotension, and
paresthesias) "pathognomonic" of amyloid disease.
In addition, the physician's delay: the delay in diagnosis of doctors is often due to
non-specificity of symptoms and sometimes the inability to consider more
symptoms seemingly unrelated to each other as an expression of the same
clinical picture (red flags). In our case, hypotension, the hyperaesthesia, heart
disease, hypertrophic CM). If taken together they would have perhaps allowed to
reach faster to the final diagnosis.
The diagnosis of amyloidosis can not be entrusted to an isolated finding biopsy
(which may be negative in a fair percentage of cases), but should be suspected
and sought assiduously, especially if, after two years of diarrhea in the absence
of other causes characteristic signs (blood pressure and heart disease,
hypertrophic). It 's hard to argue that in two years from onset, while the amyloid
fibrils continued to infiltrate the intestinal mucosa, had not caused other tissue
damage.
Major Compulsory Revisions
Pag. 2
In the description of the case (2 years of diarrhea with weight loss of 35 pounds!)
needs to be explained better the diagnostic procedure below, taking into account
the possible diagnostic hypotheses formulated and not just merely list the
imaging studies (CT and endoscopy).
In history should be better indicated if the patient has arrived to the your
observation only at the end of two years after the onset of diarrhea.
If it happened just like that, it may indicate that ".... it is unknown whether if in the
previous period had never been observed (or investigated), postural hypotension,
or if it was never highlighted proteinuria, the presence of a CM, hypertrophic
cardiomyopathy-restrictive sensorimotor peripheral neuropathy, micturition
disorders or buildings to face, macroglossia, events ecchymotic periorbital
regions, etc. (all signs or symptoms that could be addressed to the clinical
suspicion of amyloidosis).
Pag. 3
In the description it seems that the diagnosis of amyloidosis was a serendipity
("... To our surprise ...") due to a lucky ileal biopsy, with no findings previously
existing. It 'very difficult to think that in the two previous years the amyloid fibrils
have caused only the bowel involvement without other organ impairment . In our
patienr hypertrophic cardiomyopathy, and orthostatic hypotension described
represent two "red flags" of amyloid disease very likely present already for more
than 12 months, although not noticed.