Case Report:
Hyperkalemia in a patient with familial Mediterranean fever and amyloidosis
Tamara L Hoppe1,2
Aviva Y Rostas1,2
Nicole B Sitzer1,2
1
Michael G. DeGroote School of Medicine, McMaster University
University of the Negev, Be’er Sheva, Israel
2 Ben-Gurion
nicole.sitzer@medportal.ca
ABSTRACT
Familial Mediterranean Fever is a hereditary periodic fever syndrome primarily
affecting Mediterranean populations and manifesting with recurrent attacks of
fever and serositis. As with many chronic inflammatory states, amyloidosis is a
serious complication. Colchicine is used to manage FMF by reducing
inflammation and preventing secondary amyloidosis, but has several undesired
effects. We present a patient with FMF complicated by amyloidosis and renal
failure. Through this case presentation, we will discuss chronic inflammation as
an underlying cause of systemic amyloidosis.
KEYWORDS: Familial Mediterranean Fever, Amyloidosis, Colchicine, Periodic
Fever Syndrome
HISTORY
Patient X is a 62 year-old Jewish male of Iraqi descent, with a history of FMF and
consequent amyloidosis, chronic renal failure (baseline creatinine 155 mmol/L),
chronic anemia, and hypertension. As well, he has multiple sclerosis and gout.
He has a strong family history of FMF and was diagnosed in childhood. Patient X
described experiencing recurrent attacks of severe abdominal and leg pain, as
well as swelling in the calves. Although his current medications included
colchicine, this treatment was not available at the time of disease onset.
Unfortunately, due to this extended period of uncontrolled inflammation, he
developed secondary renal amyloidosis and chronic renal failure.
Prior to hospitalization, Patient X presented to his family physician with a onemonth history of diarrhea, fatigue, and weakness. Bloodwork was unremarkable,
with the exception of a potassium (K+) of 6.2 mmol/L (3.5-5). The patient was
sent to the emergency department (ED) and admitted to the internal medicine
service.
PHYSICAL EXAMINATION AND INVESTIGATIONS
Upon presentation to the ED, his vital signs were within normal limits. Both
physical examination and chest X-ray were unremarkable. Bloodwork revealed
an elevated creatinine of 195 mmol/L, urea of 9.8 mmol/L (3.0-6.5), K++ of 5.7
and hemoglobin of 98 g/L (130-180). Additionally, his creatine kinase (CK) was
elevated, but the exact value was unknown. Of note, EKG findings were
abnormal revealing peaked T waves on the chest leads consistent with
potentially arrhythmogenic hyperkalemia. The patient was urgently treated with
calcium gluconate, ventolin, and kayexalate.
FAMILIAL MEDITERRANEAN FEVER
Familial Mediterranean Fever (FMF) is an autosomal recessive disease,
characterized by recurrent paroxysmal attacks of fever (>40C) and serositis,
including peritonitis and pleuritisi. The presentation often resembles an acute
surgical abdomen, with onset frequently between 10-20 years of ageii. FMF is
most prevalent in inhabitants of the Mediterranean basin including Sephardic
Jewish, Arabic, Turkish, and Armenian populationsiii. A long-term, serious
complication of FMF is secondary amyloidosisiv, which damages multiple organ
systems including the kidneys, gastrointestinal (GI) tract, liver, spleen, heart,
thyroid and testesv. It is important to have an understanding of this disease
because Canada’s population is multicultural and immigrant-rich, and cases of
FMF may present in local hospitals. Additionally, FMF is an archetypal hereditary
periodic fever syndrome and shares complications and treatment principles with
other diseases of this type such as TNF receptor-1 periodic fever syndrome and
Hyper IgD syndrome.
FMF is caused by a mutation, typically M694V in the MEFV gene on
chromosome 16p, which results in the production of a defective Pyrin
(marenostrin) protein. Normally, Pyrin is expressed on circulating neutrophils and
acts to decrease the systemic inflammatory responsevi. However, in cases of
FMF, the mutant Pyrin protein fails to blunt the inflammatory response, producing
widespread neutrophil-dominant inflammationvii.
The current standard treatment is colchicine, a plant extract, made available in
1972. Colchicine binds a drug domain on microtubules inhibiting neutrophil
motility and blunting the inflammatory responseviii. It is absorbed in the distal
small bowel and the primary route of excretion is via the hepatobiliary system ix.
Side effects include GI upset, neutropenia, and myopathyx.
This report characterizes the types of amyloidosis as well as its clinical
manifestations. In the case presented, we also discuss the pathophysiology of
amyloidosis, renal failure, and other sequelae of FMF.
AMYLOIDOSIS
Amyloidosis includes a collection of diseases that are characterized by abnormal
protein-folding. The atypical proteins often assemble into toxic and insoluble pleated sheets with resultant systemic or organ-specific protein deposition. The
two most common subtypes of amyloidosis are of the systemic nature, and they
include light chain amyloidosis (AL) and reactive amyloidosis (AA) xi.
Light chain amyloidosis involves deposition of monoclonal Ig light chain, and
occurs primarily in multiple myeloma, monoclonal gammopathy of undetermined
significance, and Waldenström’s macroglobulinemiaxii. Reactive amyloidosis is
distinguished by deposition of serum amyloid A protein. It occurs as a
consequence of chronic inflammatory states such as chronic infection, and
various inflammatory diseases including rheumatoid arthritis, inflammatory bowel
disease and periodic fever syndromesxiii. Based on the pervasiveness of these
etiologies, reactive amyloidosis is expected to be more prevalent.
Chronic inflammation perpetuates the release of cytokines, particularly
interleukin-1, from activated macrophages. These cytokines stimulate increased
hepatocyte production of acute phase reactants, including serum amyloid A,
which is broken into smaller fragments (AA) by circulating monocytes and
macrophagesxiv. These fragments then deposit into various tissues, resulting in
tissue damagexv. Complications include heart failure, GI pathology, bowel
perforation, and renal diseasexvi. With respect to renal amyloidosis, protein
deposition may be glomerular or vascular, both impairing filtration resulting in
chronic renal failurexvii.
The diagnosis of possible amyloidosis is based on history and clinical
presentation and is then verified by a renal or rectal tissue biopsy. Under
polarized light, amyloid proteins, if present, bind to Congo red staining and will
show pathognomonic apple-green birefringencexviii.
We present a case encountered at Soroka Hospital in Be’er Sheva, Israel, a
country in the Mediterranean with a large population susceptible to FMF. The
patient described typifies the natural history, management, and complications of
FMF and amyloidosis.
ANALYZING THE INVESTIGATIONS
There are multiple possible etiologies for the acute presentation of hyperkalemia
in Patient X. He had diarrhea, likely as an adverse effect of his colchicine
treatment or as a GI manifestation of amyloidosis. The diarrhea likely led to a
volume-depleted state, exacerbating his chronic renal failure, and resulting in
hyperkalemia. Furthermore, his elevated CK, consistent with myoglobin toxicity
as an adverse effect of colchicine treatment, may have led to acute tubular
necrosis due to the toxicity of myoglobin to renal tubular cells. It was suspected
that the patient’s presentation may have been aggravated by a diet rich in
potassium.
CONCLUSION
This report used FMF as an example to illustrate the causal relationship between
chronic inflammation and amyloidosis. The knowledge gained from this case may
be applied to a host of other inflammatory states including malignancies and
various rheumatological conditions. The etiologies of amyloidosis are common,
and it is important to aggressively identify and treat chronic inflammation to
mitigate the occurrence of this preventable and devastating complication.
ACKNOWLEDGMENTS
We the authors thank Dr. Mahmud Abu-Shakra of Ben-Gurion University of the
Negev for his encouragement and guidance throughout our elective.
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Author Biographies:
Tamara Hoppe, Aviva Rostas, and Nicole Sitzer are second year medical
students at McMaster University. Prior to medical school, they studied in the
Bachelor of Sciences program at the University of Western Ontario. This past
summer, they traveled to Be’er Sheva, Israel, for an elective in International
Health and Internal Medicine at Soroka Hospital associated with Ben Gurion
University of the Negev. While abroad, they observed interesting presentations
of diseases commonly encountered in Mediterranean populations and hope to
continue to travel and work together in the future.