Gastric, Colonic, and Rectal Amyloidosis in the Setting of Familial Mediterranean Fever: A Unique Cause of Intractable Diarrhea

Familial Mediterranean fever (FMF) is a hereditary disorder characterized by episodes of fever, polyserositis, or cutaneous inflammation. The FMF attacks last 1–3 days and have no apparent triggers. Recurrent deposition of the serum amyloid A (SAA) protein in the gut can cause intractable diarrhea, dysmotility, and recurrent abdominal pain. Gastrointestinal amyloidosis is a rare, but serious, complication of FMF. In this case report, we describe a rare case of chronic diarrhea and recurrent abdominal pain due to FMF-induced gastrointestinal amyloidosis.


Introduction
Familial Mediterranean fever (FMF) is an autoinfammatory autosomal disorder that manifests as recurrent episodes of serositis and fever [1,2] or skin erythema [3].Reported to have originated in Mesopotamia 3000 years ago, FMF has a higher burden on individuals from the Mediterranean basin [2].Te Mediterranean fever (MEFV) gene, located on the short arm of chromosome 16, encodes the pyrin protein [1].Pyrin is an innate immune sensor that protects the body against infection and other harmful substances [1,2].In FMF, the pyrin infammasome assembly can be easily triggered by any stimulus, thus forcing the body into a proinfammatory state.Te production of infammatory markers, such as IL-1 and IL-18, results in serositis [1].Recurrent FMF attacks lead to continued tissue deposition of serum amyloid A (SAA) protein, an acute-phase reactant [4,5].SAA protein deposition in the gut causes gastrointestinal (GI) amyloidosis, a rare yet severe complication that often presents as chronic diarrhea and recurrent abdominal pain [4,6].Herein, we report a rare case of gastric and colorectal amyloidosis as a unique cause of intractable diarrhea in a patient with a suspected history of adultonset FMF.

Case Report
A 48-year-old Syrian man with a medical history of suspected familial Mediterranean fever (FMF), hypertension, end-stage renal disease due to hypertensive nephropathy, and a recent right kidney transplant presented to the emergency department (ED) with generalized weakness and abdominal pain.Abdominal symptoms were described as poorly localized, nonradiating, intermittent, and throbbing pain.Tese symptoms were accompanied by subjective fever, nausea, vomiting, anorexia, and unquantifable weight loss.Te patient also reported 5-6 episodes of watery diarrhea daily, even with fasting.He denied early satiety, melena, or hematochezia, recent camping, or recent international travel.He also denied any personal or family history of food sensitivity or infammatory bowel disease.Notably, the patient was seen in the ED multiple times in the preceding six months for the evaluation of vague abdominal pain, intermittent fever, and difuse joint pain.His daily home medications entailed tacrolimus 4 mg, three times daily, prednisone 5 mg, once daily, and mycophenolate 360 mg, twice daily, for immunosuppression.
In the ED, the patient's vital signs were signifcant for tachycardia, with a heart rate of 116 beats/minute.Te patient was thin-appearing and in distress due to pain.Te abdomen was soft, nondistended, and had a healed transplant scar on the right lower quadrant.Te abdomen was difusely tender on palpation, but without guarding, rigidity, or rebound tenderness.Hyperactive bowel sounds were appreciated throughout, and the digital rectal examination was normal.No rashes, palmar erythema, rheumatoid nodules, joint tenderness, or obvious joint deformities were observed.Te rest of the physical examination was unremarkable.Admission laboratory work was signifcant for hyponatremia, hyperkalemia, hypercalcemia, acute kidney injury, metabolic acidosis, leukocytosis, elevated erythrocyte sedimentation rate (ESR), and elevated ferritin (Table 1).Te urinalysis was only signifcant for trace ketones.Serum lipase level, thyroid stimulating hormone, hepatitis panel, procalcitonin, lactic acid level, transferrin, and C-reactive protein (CRP) were all unremarkable.
Computed tomography (CT) scan of the abdomen and pelvis showed no intraabdominal pathology.Renal ultrasonography revealed atrophic native kidneys.Te transplanted kidney was in the right lower abdomen and was normal in size and echotexture.No critical arterial or venous stenosis was observed.Owing to concerns for medicationinduced colitis, we switched the patient's mycophenolate to azathioprine, but the diarrhea persisted.Infectious stool workup, including Clostridium difcile, ova and parasites, Cryptosporidium, Salmonella, Shigella, and Giardia lamblia, was negative.Infammatory bowel disease workup also came back negative.Esophagogastroduodenoscopy (EGD) revealed a small hiatal hernia, bilious gastric fuid, and erythema in the gastric body and antrum.Colonoscopy demonstrated an area of moderately congested rectal mucosa and a 5 mm sessile polyp in the ascending colon (Figure 1).Random biopsies from the esophagus, stomach, colon, and rectum were obtained for histological examination, and the polyp was removed using cold biopsy forceps.Te pathology results showed esophagitis, gastritis, and proctitis.Histopathology ruled out cytomegalovirus superinfection.
While inpatient, the patient was tapered of the total parenteral nutrition and underwent a percutaneous endoscopic gastrostomy (PEG) tube placement due to severe malnutrition.With a possible diagnosis of adult-onset FMF due to recurrent episodes of serositis, fever, and abdominal pain, the patient was started on colchicine 0.3 mg, twice daily as treatment for FMF-induced gastrointestinal amyloidosis.Additional tests ruled out multiple myeloma, thyroid disease, systemic lupus erythematosus, and other rheumatological diseases (Table 1).Once the diarrhea improved, he Case Reports in Gastrointestinal Medicine was discharged home with plans for outpatient follow-up with a rheumatologist and an oncologist.Te histopathology results of the stomach body, antrum, transverse colon, and rectum biopsies returned positive for amyloid AA (Figure 2), consistent with gastrointestinal amyloidosis.A renal biopsy ruled out organ rejection and renal amyloidosis.Te patient was notifed about the results, and his colchicine dose was increased to 0.6 mg twice daily, and he continued to improve.
Te patient was readmitted after two months for PEG tube removal, and he was started on a regular diet with a mechanical soft consistency.Even though the patient declined a request for genetic testing to confrm an FMF diagnosis, he met the full major Tel-Hashomer diagnostic criteria for FMF.Tat is, he experienced recurrent episodes of serositis with fever, had biopsy-confrmed SAA amyloidosis without a predisposing disease, and improved rapidly with colchicine therapy.We diagnosed the patient with FMF and FMF-induced gastrointestinal amyloidosis.Te patient continues to follow up with our continuity clinic, and he remains on colchicine for FMF prophylaxis.No one in the patient's immediate family (grandparents, parents, siblings, and children) has similar symptoms or a documented diagnosis of FMF.

Discussion
FMF is the most frequent periodic syndrome and is characterized by recurrent attacks of polyserositis and fever [2,4].FMF attacks are acute [2] and have no identifable triggers.Fever is the most prevalent symptom among patients with FMF [1].FMF attacks may manifest as pleurisy, erysipelas-like rash, arthritis, recurrent abdominal pain, or an acute scrotum [3].Patients with M694V homozygosity have a severe form of FMF and an earlier onset [2].Tese patients experience more frequent fares and require higher doses of colchicine as a prophylaxis.Tey also have a higher incidence of complications, such as gastrointestinal (GI) amyloidosis.Amyloidosis is the extracellular deposition of misfolded fbrillar proteins in tissues, disrupting tissue anatomy and function [4,[7][8][9].GI amyloidosis often presents as recurrent abdominal pain, nausea, vomiting, weight loss, diarrhea, constipation, bleeding, fecal incontinence, dysphasia [7,10,11], or hepatomegaly [12].Gut involvement occurs in 3-8% of all cases of secondary amyloidosis cases [5].
Intractable diarrhea is the most common symptom in GI amyloidosis cases [5,11].Typically postprandial, the diarrhea is often watery.Te mechanism is not fully understood but is postulated due to autonomic neuropathy and intestinal infammation [11].Our patient presented with intractable watery diarrhea for over six months, which was found to be due to GI amyloidosis.SAA deposition in the stomach causes early satiety and reduced appetite leading to unintentional weight loss.Chronic diarrhea, malabsorption, nausea, and vomiting can also contribute to the cachexia [11].Rarely, secondary amyloidosis can manifest as lower GI bleeding, mainly in the setting of tissue ischemia.Parts of the GI tract without a collateral blood supply are the most affected [5].Hashmi et al. [5] presented an interesting case of rectal proctitis as a unique complication of secondary amyloidosis.Amyloid deposition predisposes patients to intestinal ischemia, which can cause mucosal ulcerations and vascular fragility [5].Kim et al. [13] reported a rare case of massive hematochezia in the setting of intestinal amyloidosis that was refractory to multiple arterial embolizations.Rectal involvement is very rare owing to its dual blood supply [5].Amyloid deposits in the esophageal smooth muscle and autonomic plexus often leads to delayed gastric emptying in patients with FMF.Saglam et al. [10] reported a rare case of delayed gastric emptying in a patient with FMF that improved with erythromycin treatment [10].Very rarely, amyloid proteins can be found in the liver, resulting in hepatomegaly and even portal hypertension [12].Liver transplantation has been foated as a therapeutic option in advanced cases [12].
In GI amyloidosis, routine imaging studies such as a CT scan of the abdomen may be unremarkable or show nonspecifc fndings such as bowel wall thickening, narrowing of the intestinal lumen, or loss of colonic haustrations [11,12].Upper endoscopy with biopsy of the stomach or duodenum has a higher yield of GI amyloidosis [11].Endoscopic ultrasound, push enteroscopy, and colonoscopy have been used in some cases.Congo red staining with apple-green birefringence under polarized light is the standard modality for amyloid diagnosis.Amyloid typing is essential for identifying the amyloid subtypes and choosing appropriate treatments [11].GI amyloidosis can be misdiagnosed because of its rarity and diverse clinical presentation.
Amyloidosis treatment entails identifying the etiology and managing the symptoms [9].With 92% efcacy, colchicine remains the frst-line treatment for FMF attacks and FMF prophylaxis [4].Colchicine prophylaxis prevents amyloid deposition in tissues and the resulting organopathy [2,4].Colchicine intolerance may be due to toxicity, side efects, or resistance [14,15].Isolated cases of FMFinduced gastrointestinal amyloidosis refractory to colchicine therapy have been reported in the literature.Monoclonal antibodies targeting IL-1 and IL-6 receptors are a promising alternative for these patients [15].Anakinra, a recombinant IL-1 receptor antagonist, reduces the frequency of FMF attacks and improves renal function in patient with renal amyloidosis [15].Despite limited sample sizes, Canakinumab, another IL-1 receptor antagonist, has shown almost equal efcacy as Anakinra in clinical trials [15].It is an option for patients who are intolerant to Anakinra due to its side efect profle or lack of therapeutic beneft [14,15].Tocilizumab, an IL-6 antibody, works by suppressing the pyrin infammasome complex, reducing the frequency of FMF attacks and the incidence of complications such as gastrointestinal amyloidosis [2,4].Hamanoue et al. [2] reported a case of secondary amyloidosis refractory to colchicine therapy, which was successfully treated with tocilizumab.Similarly, Aikawa et al. [4] reported an atypical case of FMF with persistent arthralgia and intractable diarrhea that was resolved with tocilizumab therapy.Tocilizumab can be considered a second or third line for patients with FMF or FMFassociated amyloidosis refractory to colchicine.

Conclusion
Although rare, gastrointestinal amyloidosis should be considered in the diferential diagnosis for intractable diarrhea in patients with confrmed or suspected FMF.Te nonspecifc nature of the symptoms can delay diagnosis or lead to unnecessary surgical interventions.

Figure 1 :
Figure 1: An endoscopic image showing a 5 mm polyp in the ascending colon (a) and an area of moderately congested mucosa in the transverse colon (b) and rectum (c and d).

Figure 2 :
Figure 2: Gastric and colorectal mucosal biopsies with H&E staining (a and b) showing pinkish proteinaceous deposits consistent with amyloid deposition.(c) An electron microscopy image showing amyloid deposits in small blood vessels and smooth muscles in the gut.

Table 1 :
Te patient's admission and pertinent laboratory values compared to the reference ranges.