EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Amyloidosis has been well known since Rudolph Virchow named the condition in the 19th century. Most physicians were aware of the association between amyloidosis to chronic suppurative conditions and multiple myeloma. However, familial Mediterranean fever, although probably as ancient as the Galenic era, was appropriately identified only in the 21st century. The nomenclature was variable throughout history, but the name “FMF” has been universally adopted since the report from Heller and colleagues in 1958. In 1967, Sokmen and Ozdemir of Ankara University published a report on 194 patients, of whom 64 had amyloidosis. Familial Mediterranean fever constituted the cause in half of the cases. Goldfinger and Ozkan demonstrated efficacy of colchicine for treatment of familial Mediterranean fever in 1972, and further studies revealed that colchicine is also efficient for prevention of amyloidosis. However, since then, several single-center and multicenter amyloid A amyloidosis studies from Turkey have been published. Almost invariably, familial Mediterranean fever is the most common cause of systemic amyloidosis. No downward trends in percentages have been observed. Recent studies have shown that cases of amyloidosis in patients with familial Mediterranean fever are decreasing. Also, cases of amyloidosis in conjunction with suppurative conditions are on the decrease worldwide. However, according to registry data from the Turkish Society of Nephrology, the percentage of incident hemodialysis patients with amyloidosis is not decreasing. The question arises: Why is a complication that is 98% preventable still causing end-stage renal disease? We believe the lack of a stable and comprehensive registry for familial Mediterranean fever, including associated cases of amyloidosis, is the reason we cannot properly answer this question. In this work, we use a historical approach to present why a familial Mediterranean fever registry is direly needed.

Key words : History of amyloidosis, Multiple myeloma, National registry, Secondary amyloidosis

Rudolf Virchow defined the term “amyloidosis” in the 19th century, and since then, most physicians involved with patients with kidney disease have become familiar with the nephrotic syndrome related to amyloidosis.1 However, the subtypes of this disorder, such as AA (secondary), AL (primary), At (senile transthyretin-related), and others, have only been recently unveiled.2 At the start of the 20th century, there were 2 distinct and well-known mechanisms leading to amyloidosis: amyloidosis related to chronic suppurative conditions and amyloidosis related to multiple myeloma.

Familial Mediterranean fever (FMF) is a disorder of unsuppressed innate immunity for which the gene for Mediterranean fever, MEFV (previously pyrin/marenostrin), on chromosome 16 is defective and results in a defective protein of the same name. The MEFV gene is then inherited through an autosomal recessive fashion with incomplete penetrance.³ Familial Mediterranean fever is characterized by recurrent attacks of fever and pain in the abdomen or chest and may lead to peritonitis, pleuritis, and pericarditis, as well as arthritis and myriad other symptoms. For 90% of patients with FMF, symptoms begin in childhood, where typical clinical presentation and robust response to colchicine confirm the diagnosis. Information from the field of genetics has been recently available but has been focused on academic rather than diagnostic purposes. People of Turkish, Arab, Jewish, or Armenian descent and people from countries with borders to the Mediterranean Sea are predominantly affected. If left untreated, FMF leads to AA amyloidosis in most cases.⁴

The history of the geographic distribution and founder effect in some countries has led to the belief that FMF may confer survival benefits for some conditions, similar to the manner in which certain survival benefits may be conferred to people with the sickle cell trait. For example, a recent study has claimed that FMF confers survival benefits against the Black Plague.⁵

Clearly, FMF has been the most common cause of amyloidosis for Turkish patients since 1967. In a recent study by Ozen and colleagues, the percentage of amyloidosis in patients with FMF decreased to 2% for patients diagnosed during 2000-2009, down from 12% for patients diagnosed during 1978-2000.⁶This improvement can be attributed to early diagnosis and regular use of colchicine. In contrast, in several reports from the hemodialysis registry of the Turkish Society of Nephrology, the percentage of amyloidosis among incident hemodialysis patients is around 1% without a significant change.^7-9

This conflict requires an explanation: FMF-related amyloidosis is decreasing, but the percentage of amyloidosis due to all causes in the hemodialysis population is not on the same decremental trend. In this study, we aimed to resolve this conflict via a historical approach.

Familial Mediterranean Fever and Related Amyloidosis in Early Turkish Medical Literature

Historically, FMF is probably as old as Galenic times. The first modern reports of FMF date back to 1900-1910. Familial Mediterranean fever has been appropriately identified only in the 21st century.¹⁰ Several names have been proposed for decades; however, after the publication of the iconic paper by Heller and colleagues in 1958, the term “FMF” prevailed globally.¹¹

The legendary nephrologist Erich Frank mentioned that amyloidosis was frequent in Istanbul, and he gave a detailed list of underlying conditions, such as osteomyelitis, chronic pyelonephritis, tuberculosis, brucellosis, malaria, and other infectious disorders. However, he did not mention FMF or any different aliases for a condition with recurrent abdominal pain attacks.¹² The first report of a Turkish FMF case is believed to be the one published by famous politician and physician Dr. Samuel Abrayeva Marmarali in 1946 as “Garip bir karin agrisi sendromu” (An enigmatic syndrome of abdominal pain).¹³

In 1967, Sokmen and Ozdemir from Ankara University Faculty of Medicine published a biopsy series in the Annals of Internal Medicine, which was the first of its kind in a universal manner for Turkish kidney biopsy literature. Of 194 patients, 64 had amyloidosis; for 51% of the amyloid cases, FMF was the culprit.¹⁴ The same duo also reported that during 1958-1968 the prevalence of FMF was 0.3% of the population.¹⁵

Rise of Colchicine and Its Impact on Turkey

In 1972, Dr. Stephen Goldfinger of Massachusetts General Hospital in Boston published a ground-breaking short communication of his 5 patients with FMF who were treated with colchicine, an alkaloid derived from the flower Colchicum autumnale.¹⁶ Ozkan and colleagues demonstrated similar success.¹⁷ All patients treated with colchicine experienced a dramatic decline in the number of painful attacks. Since then, several other large-scale studiessupported these findings. Hence, as of the late 1970s, colchicine has been the treatment of choice for FMF.¹⁸

Researchers from Hacettepe University published the success of colchicine in prevention of AA amyloidosis in 295 patients. Furthermore, after regular use of the remedy, the percentage of cases with amyloidosis decreased to 2%.¹⁹

Modern-Day Data on Familial Mediterranean Fever-Related Amyloidosis in Turkey

Meanwhile, the same group published another population estimate study that reported the prevalence of FMF to be 2.3 to 9.3 per 10 000 population.²⁰ However, the most concise study on the prevalence of FMF is dated to 2005, when the Turkish Society of Pediatric Nephrology commenced a multicenter cohort study of 2838 patients and reported the prevalence to be 1 in 1000 population and the carrier state to be 1 in 5. The mean age at diagnosis was 23 years, with a diagnostic delay of 6.9 years; 12.9% of these patients had proven amyloidosis.²¹

A more recent analysis of pediatric biopsy cohorts from Turkey showed that the percentages of AA amyloidosis in all biopsy specimens were as follows: 0.97% (1991), 1.21% (2001), and 1.12% (2008), without a clear downward trend.²² Since then, numerous single-center studies have been published, with FMF remaining Turkey’s leading cause of AA amyloidosis. Furthermore, according to registry data from the Turkish Society of Nephrology, 1% to 2% of end-stage renal disease in Turkey is attributed to FMF-related amyloidosis, again without an apparent downward trend.⁹

Although treatment with interleukin-1 inhibitors has emerged as a treatment option for patients with colchicine intolerance or resistance, we have not achieved zero amyloidosis.²³ Secondary amyloidosis due to FMF still occurs. No clear downward trend has been observed in the past 20 years. Familial Mediterranean fever remains Turkey’s leading cause (20%-70%) of AA amyloidosis. Although some research suggests that patients with newly diagnosed FMF have a 2% risk of amyloidosis, this low risk is most likely attributable to colchicine rather than our efforts.

Since the Turkish Society of Nephrology registry does not discriminate between FMF-related amyloidosis and unrelated amyloidosis, we can only hypothesize. Amyloidosis due to suppurative causes should be decreasing as the global trend is toward better hygiene and new developments for treatment of infectious diseases. The aforementioned study suggests that a lower percentage of amyloidosis in FMF patients should result in lower total number and percentage of amyloidosis in the hemodialysis population.²³ We have not seen such a downward trend, so there are 2 possibilities. The number of patients with FMF has increased significantly, or there is treatment failure due colchicine nonadherence, ineffectiveness, or lack of an early diagnosis.

To address this issue, we began a meticulous quest for data. Unfortunately, we have not been able to gather sufficient data on the following details: (1) the total number of patients with FMF, (2) the number of those patients with amyloidosis (proven and presumed), (3) the number of patients with colchicine nonadherence, (4) colchicine resistance in FMF patients, (5) the total number of AA amyloidosis cases and the underlying etiologies, (6) the current prevalence of FMF and FMF-related amyloidosis, and (7) the modern-day patient characteristics and diagnostic delay.

Finally, since we do not have answers to these questions, it is impossible for us to conclude that we, as physicians, are doing a proper job of diagnosis and treatment of FMF, hence abolishing the risk of amyloidosis.

We perhaps lack knowledge on these matters because we do not have a stable FMF registry. In addition, cases without amyloidosis are currently being followed up in rheumatology clinics. Unfortunately, some patients have received a presumed diagnosis of amyloidosis without a confirmatory kidney biopsy or other tissue biopsy.

Our proposed plan is the foundation of a joint national registry for nephrologists and rheuma-tologists. Public and physician education should be the other pillars of our battle against FMF-related amyloidosis.

Volume: 21 Issue: 6 June 2023 - Supplement - 2

FULL TEXT