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 ::  Abstract
 :: Introduction
 :: Case Report
 :: Discussion
 :: Conclusion
 ::  References
 ::  Article Figures
 ::  Article Tables

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  Table of Contents     
CASE REPORT
Year : 2022  |  Volume : 68  |  Issue : 4  |  Page : 239-242

Chronic diarrhea - The poetic masquerade


1 Department of Internal Medicine, Aster Medcity, Kochi, Kerala, India
2 Department of Medical Gastroenterology, Aster Medcity, Kochi, Kerala, India
3 Department of Neurology, Aster Medcity, Kochi, Kerala, India

Date of Submission16-Dec-2021
Date of Decision08-Jun-2022
Date of Acceptance15-Jun-2022
Date of Web Publication04-Nov-2022

Correspondence Address:
S Bhattacharjee
Department of Internal Medicine, Aster Medcity, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpgm.jpgm_1169_21

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 :: Abstract 


Chronic diarrhea, by definition, is the passage of loose/liquid stools, with increased frequency (more than three times/day), or an output of over 200 g/day, lasting for a duration of four or more weeks. The clinical approach to identify the cause of chronic diarrhea generally depends on the local socioeconomic status. In high-income countries, systemic causes such as irritable bowel syndrome (IBS), inflammatory bowel disease, malabsorption syndromes (lactose intolerance/coeliac disease) are primarily considered. In mid- to low-income countries, infective causes like chronic bacterial, mycobacterial, fungal infections, HIV, bowel cancer are considered before systemic causes/malabsorption syndromes. Amyloidosis, more accurately, reactive amyloidosis is one of the rarer causes of chronic/persistent diarrhea. Inflammatory colitis secondary to POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) as a cause for chronic diarrhea has been reported only in a handful of cases and is often missed. We present such a case of chronic diarrhea in a middle-aged man, who was eventually diagnosed to have POEMS syndrome.


Keywords: Pathophysiology of chronic diarrhea, POEMS syndrome, POEMS syndrome with polyclonal gammopathy


How to cite this article:
Bhattacharjee S, Siyad I, Maramattom B V. Chronic diarrhea - The poetic masquerade. J Postgrad Med 2022;68:239-42

How to cite this URL:
Bhattacharjee S, Siyad I, Maramattom B V. Chronic diarrhea - The poetic masquerade. J Postgrad Med [serial online] 2022 [cited 2022 Nov 30];68:239-42. Available from: https://www.jpgmonline.com/text.asp?2022/68/4/239/360452





 :: Introduction Top


POEMS syndrome was first described by Crow in 1956 and then by Fukase in 1968. Later, in 1980, Bardwick et al., coined the acronym 'POEMS' syndrome based on the 5 dominant features of the disease—polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. However, the acronym does not capture the entirety of its clinical manifestations.[1]

POEMS syndrome is described as a paraneoplastic syndrome, in the background of a plasma cell dyscrasia/neoplasm. Plasma cells disorders range from subclinical monoclonal gammopathy of unknown significance to malignant systemic disorders such as multiple myeloma and amyloidosis, and POEMS syndrome.[2] Typically, the plasma cell disorder (PCD) in POEMS syndrome is said to be IgG or IgA, lambda chain restricted.[3] However, atypical presentations with biclonal gammopathy/polytypic/kappa chain restriction have also been described.[4],[5],[6]

In 2019, the diagnostic criteria for POEMS syndrome were updated. A diagnosis of POEMS syndrome required the presence of three of the major criteria, two of which should be polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria. The major criteria being polyradiculoneuropathy, clonal PCD, sclerotic bone lesions, elevated vascular endothelial growth factor (VEGF), and the presence of Castleman disease. The minor criteria include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis [Table 1].[7]
Table 1: Criteria for diagnosis of POEMS syndrome (2019 update)[7]

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We present a case of POEMS syndrome with biclonal gammopathy, with diarrhea as the presenting feature. To the best of our knowledge, only a handful of cases of POEMS syndrome with biclonal gammopathy have been reported, with chronic diarrhea as the presenting feature being even more rare.


 :: Case Report Top


We present the case of a 49-year-old man, a travelling monk, who presented to our center with a history of diarrhea for one-and-half years. He also complained of generalized weakness with a predominant proximal muscle weakness of bilateral lower limbs of two months.

Diving into his history revealed that his symptom of diarrhea was not associated with upper gastrointestinal (GI) symptoms, abdominal bloating, or pain abdomen. His stools were of small volume, watery in nature, and were not mixed with blood or mucus. He passed stools on an average of 6–10 times a day. Diarrhea was not associated with food intake and was present even on fasting. He also gave a history of loss of appetite and significant weight loss (approximately 12 kg over 10 months). He was previously evaluated at multiple centers for diarrhea, where blood investigations, along with upper GI endoscopy and colonoscopy were performed and was reported to be normal. He was given a diagnosis of irritable bowel syndrome (IBS) and was treated conservatively.

About two months prior to presenting to our center, he developed progressive proximal muscle weakness of bilateral lower limbs. He also developed paresthesia—glove and stocking numbness till level of mid-thigh, change in complexion of skin and bilateral lower limb swelling in the two months. There was no history of fever, night sweats, abdominal pain, or distention. There was no history of consumption of indigenous medications. There was no history of addictions or multiple sexual partners. He had a background history of hypothyroidism and asthma, which were well controlled with medications.

Clinical examination at our center revealed a slim (43 kg), conscious, and oriented gentleman with pallor, clubbing, bilateral painless pitting edema till the level of mid-shin and dry hyperpigmented skin more noticeable over the sacral area. There were no palpable lymph nodes. Systemic examination revealed hepatosplenomegaly. Neurological examination revealed a mild weakness of proximal muscles of lower limb (4/5) with full power distally and normal reflexes. Sensory examination showed distally reduced sensation to touch, pain, and vibration in upper and lower limbs. He also had hypotension (90/60 mmHg) on presentation.

His initial blood investigations revealed mild anemia (hemoglobin 10 g/dL), hyperkalemia (S. potassium 6.6 mg/dL), elevated S. creatinine (1.75 mg/dL) and a normal liver, thyroid function tests. Chest X-ray, electrocardiography and echocardiography were normal. Serology for HIV, hepatitis B, and syphilis was negative. Stool examination did not reveal any parasites, ova/cysts, and stool for occult blood was negative. Clostridium difficile toxins were negative. Ultrasonography of the abdomen revealed mild renal parenchymal disease with reduced renal size bilaterally. Computed tomography (CT) imaging of abdomen showed hepatomegaly (span 20 cm) with periportal halo and enlarged lymph nodes (size 10 mm) in porta hepatis [Figure 1]. There was also mild splenomegaly (span 12 cm), with minimal perisplenic fluid collection. Repeat upper GI endoscopy and colonoscopy at our center was normal and biopsy samples were taken. Nerve conduction studies revealed a predominantly demyelinating, sensorimotor pattern, affecting both upper and lower limbs. Serum ANA profile was negative.
Figure 1: CT Abdomen imaging showing hepatomegaly (yellow arrow) and splenomegaly (green arrow)

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In view of persistently low blood pressure with hyperkalemia, short Synacthen test was performed, which showed a reduced response suggestive of adrenal insufficiency.

During hospital stay, the patient developed moderate ascites and pleural effusion. A diagnostic ascitic fluid tap was performed, which revealed elevated (serum ascites albumin gradient) of 1.85 g/dL and no evidence of atypical/malignant cells. Endoscopic biopsy reports from the rectum revealed cystic dilatation of crypts with patchy inflammation and crypt abscess formation—consistent with colitis cystica superficialis [Figure 2]. However, biopsy specimen from the duodenum revealed no significant pathology and was negative for Congo red staining (for primary systemic amyloidosis).
Figure 2: (a) Endoscopic biopsy specimen of rectum with hematoxylin and eosin staining, at 10× magnification.(b) An 100× magnified image of endoscopic biopsy specimen of rectum. The crypts show cystic dilatation with patchy inflammation and crypt abscess formation—consistent with colitis cystica superficialis

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As periportal lymph node biopsy is an invasive procedure, positron emission tomography (PET)/CT scanning was performed which revealed multiple mediastinal, splenic, hilar, peripancreatic, para-aortic, aortocaval, and right common iliac and bilateral inguinal nodes; however, they were all non-avid. This made a neoplastic entity unlikely.

We now had a constellation of seemingly unrelated symptoms—

  1. Neuropathy—Peripheral neuropathy
  2. Organomegaly—Hepatosplenomegaly
  3. Endocrinopathy—Adrenal Insufficiency, Hypothyroidism
  4. Skin changes—Hyperpigmentation, dry skin
  5. Chronic Diarrhea


It was at this point that we realized POEMS syndrome was a possibility and decided to send high-resolution serum protein electrophoresis (SPE) with immunofixation. SPE showed elevated kappa (151 mg/L; normal range 3.3–19.4 mg/L) as well as elevated lambda light chains (57.2 mg/L; normal range 5.7–26.3 mg/L) with increased kappa to lambda ratio (2.6; normal range 0.26–1.65), suggestive of monoclonal gammopathy. Surprisingly, immunofixation showed biclonal gammopathy in the beta globulin region, identified as IgG with kappa and lambda, and IgA with lambda [Figure 3]. Immunoglobulin quantification revealed IgG 1786 mg/dL (normal 600–1400 mg/dL), IgA 573 mg/dL (normal 90–450 mg/dL) and IgM 75 mg/dL (normal 50–200 mg/dL). To further support a diagnosis of POEMS syndrome, VEGF levels were sent, which was significantly elevated- 1857 pg/mL (normal 31–86 pg/mL). Bone marrow biopsy with immunohistochemistry was performed, which showed polyclonal plasmacytosis (13%) with CD-138 cluster positivity with kappa and lambda chains. A multiple myeloma fluorescent in situ hybridisation) panel was sent, which was also negative.
Figure 3: Immunofixation showing M bands in the beta globulin region identified as IgG with kappa and lambda (green arrows) and IgA with lambda (red arrows)

Click here to view



 :: Discussion Top


Infrequent systemic causes of chronic diarrhea like amyloidosis, light chain deposition disease, malignancy should be considered in the differential diagnosis, once the common causes are ruled out.[8],[9] Our patient fit the diagnostic criteria for POEMS syndrome. He had three major criteria—polyradiculoneuropathy, clonal PCD, and elevated VEGF, and four minor criteria—organomegaly, endocrinopathy, skin changes, and extravascular fluid overload.

As mentioned earlier, POEMS syndrome is described to be a paraneoplastic syndrome in the background of plasma cell dyscrasia. However, the exact pathophysiology is still unclear. In the early- to mid-1990s, it was found that all “M” components in patients with POEMS syndrome had a lamda-light chain. An IgG M-component was found more frequently in patients with solitary osteosclerotic lesions. An IgA M-component was found more frequently in patients without bone lesions.[10] Our patient presented with a biclonal gammopathy, which is a rare association with POEMS syndrome.

More recent evidence points to the cytokine overproduction associated with POEMS syndrome as a cause for the symptoms. Patients generally present with high levels of IL-1a (interleukin), IL-6, TNF alpha (tumor necrosis factor). The presence of high levels of VEGF is a relatively new find and explains symptoms of extravascular fluid overload and chronic diarrhea due to increased vascular permeability.[11]

Reactive amyloidosis has also been described in association with POEMS syndrome. The GI deposition of the amyloid A protein is thought to be another possible reason for chronic diarrhea in POEMS syndrome. Though reactive amyloidosis is generally associated with IgM gammopathy with kappa chain deposition, various combinations have been previously described.[12]

In our case, though intestinal biopsy did not stain positive for Congo-red staining, we strongly believe that elevated VEGF and reactive amyloidosis are the two main driving factors for patients presenting with chronic diarrhea in POEMS syndrome. Amyloid deposition also explains the cause for hyperkalemic renal disease in our patient.

Unfortunately, there is no specific treatment for POEMS syndrome. Treatment options available largely target symptom management and slowing down the progression. Corticosteroids help in symptom control temporarily, but alkylating agents (cyclophosphamide, melphalan) are the mainstay of treatment, depending on toxicity profile. Lenalidomide is commonly used due to its manageable toxicity risk.[7] Anti-VEGF therapy (bevacizumab) has shown promising results and VEGF levels can be used to prognosticate progression of disease. Patients with osteosclerotic bone lesions benefit from autologous peripheral blood stem cell transplantation (PBSCT). Residual disease after PBSCT is treated with radiotherapy.[13]

Our patient was started on intravenous cyclophosphamide therapy with corticosteroids. An essential but often overlooked area of treatment is psychiatry counselling. This helps the patient to accept the disease prognosis and helps to manage symptoms of depression and social embarrassment. On a three-month follow-up, his symptoms of diarrhea had significantly improved. However, the patient was lost to follow-up thereafter.


 :: Conclusion Top


Chronic diarrhea is a cause for extreme distress and social embarrassment to patients. When initial investigations rule out infective causes, and no gross abnormality in endoscopy/colonoscopy is found, patients are often falsely labelled to have IBS. A detailed history, multisystemic investigation and a keen intuition are essential to clinch the more rare but sinister causes for chronic diarrhea. Among these amyloidosis, light chain deposition disease, POEMS syndrome, and malignancy need to be considered. Though our patient received a grave prognosis in the form of POEMS syndrome, he was most happy to be discharged from our center with an answer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 :: References Top

1.
Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Baltimore) 1980;59:311-22.  Back to cited text no. 1
    
2.
Byun JM, Kwon YN, Koh Y, Yoon SS, Sung JJ, Kim I. Distinctive patterns of peripheral neuropathy across the spectrum of plasma cell disorders. Sci Rep 2019;9:16769.  Back to cited text no. 2
    
3.
Dao LN, Hanson CA, Dispenzieri A, Morice WG, Kurtin PJ, Hoyer JD. Bone marrow histopathology in POEMS syndrome: A distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients. Blood 2011;117:6438-44.  Back to cited text no. 3
    
4.
De D, Halder S, Datta SS. POEMS syndrome with biclonal gammopathy: A rare association. J Clin Diagn Res 2017;11:XD12-3.  Back to cited text no. 4
    
5.
Pulivarthi S, Gurram MK. An atypical presentation of POEMS syndrome with IgG kappa type M protein and normal VEGF level: Case report and review of literature. J Cancer Res Ther 2018;14:679-81.  Back to cited text no. 5
    
6.
Ham JY, Suh JS, Lee WK, Song KE. POEMS syndrome with IgG-λ/IgA-κ biclonal gammopathy and abnormal serum free light chain ratio: A case report. Ann Clin Lab Sci 2015;45:702-6.  Back to cited text no. 6
    
7.
Dispenzieri A. POEMS syndrome: 2019 Update on diagnosis, risk-stratification, and management. Am J Hematol 2019;94:812-27.  Back to cited text no. 7
    
8.
Otagiri S, Nakajima S, Katsurada T, Sakurai K, Yamanashi K, Ara T, et al. Chronic diarrhea as the presenting feature of amyloidosis with multiple myeloma: A case report diagnosed by a myocardial biopsy. Intern Med 2021;60:1197-203.  Back to cited text no. 8
    
9.
Pfluecke C, Ulbrich S, Ibrahim K, Geiger KD, Strasser RH, Wunderlich C. Chronic diarrhea as the initial clinical manifestation of light-chain amyloidosis with cardiac involvement despite negative duodenal and rectal biopsies. Exp Clin Cardiol 2013;18:148-50.  Back to cited text no. 9
    
10.
Soubrier MJ, Dubost JJ, Sauvezie BJ. POEMS syndrome: A study of 25 cases and a review of the literature. French Study Group on POEMS syndrome. Am J Med 1994;97:543-53.  Back to cited text no. 10
    
11.
Vaz JA, Frada L, Soares MM, Mello E Silva A. POEMS syndrome: An atypical presentation with chronic diarrhoea and asthenia. Eur J Case Rep Intern Med 2019;7:001241.  Back to cited text no. 11
    
12.
Kihara Y, Hori H, Murakami H, Hatakeyama Y, Yoshikawa I, Hamada T, et al. A case of POEMS syndrome associated with reactive amyloidosis and Waldenström's macroglobulinaemia. J Intern Med 2002;252:255-8.  Back to cited text no. 12
    
13.
Li J, Zhou DB. New advances in the diagnosis and treatment of POEMS syndrome. Br J Haematol 2013;161:303-15.  Back to cited text no. 13
    


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