Chronic diarrhea - The poetic masqueradeS Bhattacharjee1, I Siyad2, BV Maramattom3
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
Keywords: Pathophysiology of chronic diarrhea, POEMS syndrome, POEMS syndrome with polyclonal gammopathy
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.
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. Typically, the plasma cell disorder (PCD) in POEMS syndrome is said to be IgG or IgA, lambda chain restricted. However, atypical presentations with biclonal gammopathy/polytypic/kappa chain restriction have also been described.,,
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].
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.
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.
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).
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—
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.
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., 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. 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.
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.
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. 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.
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.
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.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]