2.9 Evidence Behind the Case

Chart finding	The claim the module makes	Supporting evidence	How strong?
Markers high between attacks (Clue #2) Chapters 6, 7	In FMF, acute-phase reactants — CRP, ESR and especially serum amyloid A — are often raised in the symptom-free intervals between attacks (subclinical inflammation); SAA identifies it best, and the 2024 EULAR/PReS update makes normal between-attack markers a treatment target. Honesty flag: canon gives no childhood values and dates the clue only ‘across these years’; serum amyloid A was a research measurement in the 1980s, so the module never places an SAA value on a 1984–1987 visit.	PubMed 31524848 (SAA and occult inflammation, J Clin Rheumatol 2021) · PMC4191367 · An update on FMF 2023 (PMC10253709) · EULAR/PReS 2024 update (PubMed 40234174)	FMF finding strong; its childhood dating — flagged
SAA as the raw material of AA amyloid Chapters 4, 7	Persistently raised SAA is the precursor of AA amyloidosis, FMF’s most feared complication; higher between-attack acute-phase levels predict amyloidosis, and the SAA1 genotype modifies the risk. In Stina’s story AA amyloid is found twice in 2026, both after the diagnosis (gut biopsy re-stained in June; kidney biopsy in the summer); the module says only that the slow fuse may already have been burning.	PubMed 17103173 (Rheumatol Int 2007) · PubMed 12687559 (MEFV and SAA1 genotypes, 2003) · GeneReviews NBK1227	Cohort and case-control — strong; ‘burning in childhood’ — hindsight, flagged
SAA rides on HDL Chapter 4	Circulating SAA travels almost entirely on high-density lipoprotein; in a strong acute phase it can become HDL’s main apolipoprotein, displacing ApoA-I and changing what the particle does. The lipoprotein fleet itself — chylomicron, VLDL → IDL → LDL, HDL — is textbook physiologyThe study of how the body functions..	Benditt and Eriksen 1977 · Sack 2018 (review) · OpenStax A&P 2e, Chapter 24	Biochemistry — strong
CRP, the liverA large organ that produces bile, detoxifies blood, and stores nutrients. and the acute-phase response Chapters 5, 6	IL-6, with IL-1β and TNF, drives hepatocytesLiver cells responsible for detoxification, metabolism, and bile production. to make CRP (a pentamer of five identical subunits that rises within hours, peaks around two days and has a half-lifeTime for hormone levels to reduce by half. near nineteen hours), SAA and fibrinogen plasma protein converted into fibrin during blood clotting., and to make less albumin; ESR is a test that rises with fibrinogen and globulins, not a protein. CRP was described in 1930.	Tillett and Francis 1930 · Gabay and Kushner 1999 · Pepys and Hirschfield 2003	Reviews — strong
Albumin down, globulins up — the protein gap Chapters 5, 7	Albumin is a negative acute-phase protein, so chronic inflammation lowers it while immunoglobulins(Ig) Antibodies: Proteins produced by the immune system to target specific antigens. and other globulins rise, flipping the albumin-to-globulin ratio (normally above about 1). Honesty flag: the flip is nonspecific — chronic infection, liver and kidney disease and a monoclonal protein (MGUS, found at forty and run in Blood, Module 14) all do it; the module shows the gap, not its cause.	Gabay and Kushner 1999 · OpenStax A&P 2e, Chapter 18	Physiology strong; what her gap meant — open, flagged
Pyrin variants work too easily — they do not misfold Chapters 6, 7	Pyrin (781 amino acids, five domains) is held quiet by phosphorylationaddition of a high-energy phosphate to a compound, usually a metabolic intermediate, a protein, or A and 14-3-3 binding and released when RhoA is inactivated; FMF-associated variants lower that thresholdThe minimum voltage needed to trigger an action potential. — gain of function — in a protein that still folds. The textbook variants cluster in the B30.2 domain, whose crystal structure shows residue 694 on the surface (PDB 2WL1). K⁺ efflux is the trigger of a different sensor, NLRP3. MEFV was identified in 1997.	Park et al. 2016 · Van Gorp et al. 2016 · Weinert et al. 2009 · French FMF Consortium 1997 · International FMF Consortium 1997 · UniProt O15553	Mechanism — strong (cell, mouse and structural studies)
Residue 694 — the textbook variant in a real structure Chapter 7 (narrator; the genotype is Module 4’s reveal)	The variant every reference describes, M694V (the textbook variant), sits in the B30.2 domain resolved at 1.35 Å in PDB 2WL1 (residues about 586–776). Honesty flag: Stina’s own changed copy is a different one; where it sits — and what one copy can do — is Module 4’s Chart Reveal, and not every MEFV variant lies inside this crystal structure.	Weinert et al. 2009 · RCSB PDB 2WL1 · Infevers registry	Structure — strong; its relevance to her — withheld until Module 4, flagged
AA amyloid — the true misfolding Chapter 7	AA amyloid fibrils are built from N-terminal fragments of SAA1 stacked in cross-β sheets; cryo-EM of fibrils taken from patient tissue shows the stacked layers (PDB 6MST). They stain with Congo red and show apple-green birefringence under polarizedA resting neuron’s membrane with a more negative charge inside than outside. light. Misfolded proteins can also be cleared and go missing instead — CFTR ΔF508 in cystic fibrosis, the site’s Matilda case.	Liberta et al. 2019 · RCSB PDB 6MST · OpenStax A&P 2e, Chapter 3	Structure and pathology — strong
Colchicine — an alkaloid that also prevents amyloid Chapter 6	Colchicine (C₂₂H₂₅NO₆, about 399 Da) is a tricyclic alkaloid from the autumn crocus, small and fat-soluble enough to enter cellsThe basic structural and functional units of life., where it binds tubulin and stops microtubules assembling. It has been the standard FMF treatment since the early 1970s and prevents AA amyloidosis; its margin between dose and poison is narrow.	Goldfinger 1972 · Zemer et al. 1986 · EULAR/PReS 2024 update · PubChem CID 6167	Trials and guidelines — strong
Lipin-2 — a lipid enzyme that restrains NLRP3 Chapter 4	Lipin-2 (LPIN2) is a phosphatidic acidA substance that releases hydrogen ions (H⁺) in solution. phosphatase: it turns phosphatidic acid into diacylglycerol, the branch point for triglycerides and the main membrane phospholipids. Without it, macrophages over-activate the NLRP3 inflammasome, a second route to the same IL-1β; loss of both copies causes Majeed syndrome (described 1989; about 35–40 patients reported). Honesty flag: Stina carries one LPIN2 variant — a carrier state used to ask a question — and the idea that one changed copy of each gene could add up in one person is this course’s hypothesis, not a published finding.	Lordén et al. 2017 · Ferguson et al. 2005 · Majeed et al. 1989	Mechanism — strong (cell and mouse); the two-gene model — hypothesis, flagged
What a 1984–1987 lab could measure Chapters 1, 6	An ER of the mid-1980s could report electrolytes, glucoseA simple sugar that is the main source of energy for cells., urea, a blood count and an ESR; CRP assays existed but were not a routine test for a child’s belly pain; serum amyloid A was a research measurement; the human IL-1β cDNA was cloned in 1984; MEFV was unknown until 1997. Honesty flag: this is general laboratory history, hedged — canon records only ‘the X-ray and the blood’, ‘they took blood’ and ‘blood and X-ray and nothing’.	Auron et al. 1984 · Tillett and Francis 1930 · French FMF Consortium 1997 · OpenStax A&P 2e, Chapter 26	History — moderate, hedged
‘No organic cause’ — rare disease and the psychiatric label Chapters 1, 5, 7	Being told the problem is psychological is a near-shared experience in rare disease: a German expert Delphi study named stigmatization as psychosomatic a typical experience, and in an autoinflammatory-disease survey psychosomatic disorder was the single most common misdiagnosis. Recurrent belly pain with a measured fever is not, on its own, a functional diagnosis. Honesty flag: the module does not say her pain had no psychological part; it says a fever is organic.	Blöß et al. 2017 · Rech et al. 2024	Survey and Delphi — moderate

A child with recurrent belly pain and fever has a wide differential, and the commonest answers are infections and surgical emergencies. ‘No organic cause’ is a diagnosis of exclusion that has to explain the fever too — functional abdominal pain does not raise a temperature. The module’s reasoning applies to the pattern; these are the neighbors to keep in mind.

Links checked September 2026.

1. The value of serum amyloid A levels in familial Mediterranean fever to identify occult inflammation during asymptomatic periods. J Clin Rheumatol 2021 (PubMed 31524848).

2. Can serum amyloid A level be used to support the FMF diagnosis? Pediatr Rheumatol Online J (PMC4191367).

3. The value of acute-phase reactants for predicting familial Mediterranean fever-associated amyloidosis: a case-control study. Rheumatol Int 2007 (published online 2006; PubMed 17103173).

4. Contribution of MEFV and SAA1 genotypes to amyloidosis and disease severity in familial Mediterranean fever. 2003 (PubMed 12687559).

5. An update on familial Mediterranean fever. 2023 (PMC10253709).

6. EULAR/PReS endorsed recommendations for the management of familial Mediterranean fever: 2024 update. Ann Rheum Dis 2025 (PubMed 40234174).

7. Familial Mediterranean Fever. GeneReviews®, NCBI Bookshelf NBK1227. University of Washington, Seattle (initial posting 2000; revised since).

8. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25–31.

9. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797–807.

10. Weinert C, Grütter C, Roschitzki-Voser H, Mittl PRE, Grütter MG. The crystal structure of human pyrin B30.2 domain: implications for mutations associated with familial Mediterranean fever. J Mol Biol 2009;394:226–236 (PDB 2WL1).

11. Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17:914–921.

12. Van Gorp H, et al. Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation. Proc Natl Acad Sci USA 2016;113:14384–14389.

13. Liberta F, et al. Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids. Nat Commun 2019;10:1104 (PDB 6MST).

14. Lordén G, et al. Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptorA structure that detects stimuli. activation. J Exp Med 2017;214:511–528.

15. Ferguson PJ, et al. J Med Genet 2005;42:551–557 (LPIN2 identified as the gene for Majeed syndrome).

16. Majeed HA, et al. Congenital dyserythropoietic anemiaA condition characterized by a deficiency of red blood cells or hemoglobin, leading to reduced oxyge and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 1989;115:730–734.

17. Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med 1972;287:1302.

18. Zemer D, et al. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 1986;314:1001–1005.

19. Auron PE, et al. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci USA 1984;81:7907–7911.

20. Tillett WS, Francis T Jr. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1930;52:561–571.

21. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–454.

22. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003;111:1805–1812.

23. Benditt EP, Eriksen N. Amyloid protein SAA is associated with high density lipoprotein from human serum. Proc Natl Acad Sci USA 1977;74:4025–4028.

24. Sack GH Jr. Serum amyloid A — a review. Mol Med 2018;24:46.

25. Blöß S, et al. Diagnostic needs for rare diseases and shared prediagnostic phenomena: results of a German-wide expert Delphi survey. PLoS One 2017;12:e0172532 (as cited in the diary’s evidence section A cut or slice of the body or an organ for study.).

26. Rech J, Schett G, Tufan A, et al. Patient experiences and challenges in the management of autoinflammatory diseases — data from the international FMF & AID Global Association survey. J Clin Med 2024;13(5):1199. doi:10.3390/jcm13051199.

27. Infevers: the registry of hereditary autoinflammatory disorder mutations — MEFV (variant classifications).

28. OpenStax Anatomy & Physiology 2e: Chapter 2 (The Chemical Level of Organization), Chapter 3 (The Cellular Level of Organization), Chapter 18 (The Cardiovascular System: Blood), Chapter 24 (Metabolism and Nutrition), Chapter 26 (Fluid, Electrolyte, and Acid–Base Balance).

Standing reference anchors: EULAR/PReS FMF management: 2024 update · GeneReviews: FMF · Infevers — MEFV registry