◐General Nephrology

Cryoglobulinemia

GN約 8 分鐘8 個章節

1.Cryoglobulin#

  • <37℃會沉澱(不論是plasma or serum; 若只在plasma降溫會沉澱叫cryofibrinogen)
  • Immunoglobulins or (Immunoglobulins+complements)
    • 有cryoglobulinemia很少有cryoglobulinemia syndrome
      • Prevalence:clinically-significant cryoglobulinemia:1/10W
        • 但HCV 40-65%, HIV 15-20%, (HCV+HIV) 65%, AIR 20%有cryoglobulin(代表一大堆人有cryoglobulin卻沒有S/S)

2.Types#

  • Type I(10-15%)
    • Monoclonal Ab:多為IgG or IgM; 但也可以是IgA or light chain
      • 非IC deposit-->no decreased complement but可hyperviscosity syndrome
      • From
        • M(B cells系列):(MM, WM, CLL...) >>> MGUS
  • Type II(mixed cryoglobulinemia)(50-60%)
    • Polyclonal IgG and monoclonal IgM(against the IgG; =rheumatoid factor)
      • IC deposit in BV-->vasculitis(small vessel leukocytoclastic vasculitis)-->C4↓↓, C3↓
      • From
        • I(主):HAV, HBV(MGN, MPGN, cryoglobulinemia, IgAN), HCV(MPGN, cryoglobulinemia, MGN, MCD, collapsing FSGS, TMA, TIN, fibrillary GN, immunotactoid GN(?)), EBV(MGN, cryoglobulinemia, FSGS), CMV(cryoglobulinemia, collapsing FSGS), HIV(MCD, collapsing FSGS, MPGN/cryoglobulinemia, lupus-like GN, IgAN), B19(collapsing FSGS, cryoglobulinemia), IE, streptococcus, fungus, malaria(MPGN, cryoglobulinemia, MGN...), Ameba
        • I:SLE, Sjogren, RA, PAN
        • M:B cell lymphoma, solid cancers
          • HCV>>>AIR>idiopathic>LPD>other infections
  • Type III(也是mixed cryoglobulinemia)(25-30%)
    • Polyclonal IgG and polyclonal IgM
      • IC deposit in BV-->vasculitis(small vessel leukocytoclastic vasculitis) -->C4↓↓, C3↓
      • From
        • I:as above, 尤其HCV(仍多)
        • I::as above
        • M:lymphoproliferative malignancies
          • HCV>>AIR>>idiopathic>other infections
  • 之所以HCV佔一大部分, 部分也跟liver disease/cirrhosis之後清不掉Ab有關

3.S/S of type I cryoglobulinemia#

  • 大多沒症狀, 若有症狀多以hyperviscosity syndrome/thrombosis表現, 如Raynaud, Gangrene/acrocyanosis, livedo reticularis, purpura
    • Arthralgia, renal, PNS也可不過比mixed cryoglobulinemia少見

4.S/S of mixed cryoglobulinemia(有症狀者的比例)(多為constitutional, non-specific S/S; 感覺就是一些慢性發炎,血管炎症狀)(mean 60 y/o, 多好好壞壞)#

  • Meltzer's triad(25-30%)
    • Weakness, palpable purpura, arthralgia
  • Weakness and fatigue(80%)
  • Lower limbs palpable purpura(80%), ulcers(10%)
  • Raynaud's phenomenon(35%)
  • Arthralgia(70%)(多下肢PIP, MCP, ankles, knees)/Myalgia(common); but arthritis/myositis少見
  • PNS(polyneuropathy為主)(60%)
  • Hepatosplenomegaly==>thrombocytopenia; lymphadenopathy
  • Renal disease(20-30%)(as below)
  • Increased NHL(B cell)(<10%, 多type II, 多occur after 5-10 yrs after diagnosis)
    • 因為↑BAFF
  • Sicca syndrome(30%)
  • Rare:CNS, lung(small airways disease and impairment DLCO)

5. Renal disease#

  • Average 2.5yr after disease onset(0-28 yrs)

  • GN(可isolated proteinuria~nephrotic syndrome or nephritis syndrome...; 可ESRD)(和一般MPGN類似?不過似乎是indolent, slow course, 病人大多死於infection, cardiac diseases...)

    • Microscopic hematuria + non-nephrotic range proteinuria +/- renal insufficiency:40%
    • Nephrotic syndrome +/- renal insufficiency:20%
    • Acute renal failure:10%
    • AGN:15%
    • HTN:65%
    • CKD without significant U/A abnormalities:13%(?!!)

  • Pathology

    • >80%為MPGN; others:vasculitis with fibrinoid necrosis, intraglomerular hyaline thrombi(小心SLE也可), mesangial proliferative GN (這些可以一起出現)

      • More specific for cryoglobulin-induced disease if(below)

        • Intraluminal thrombi composed of precipitated cryoglobulins(PAS(+))

        Capillary microthrombi in mixed cryoglobulinemia

  • Diffuse IgM deposition in the capillary loops

  • Subendothelial deposits on EM that often have a clear substructure with a characteristic "fingerprint" pattern of cryoprecipitates(as below)(25-40nm, 所以要D/D immunotactoid GN; cryoglobulin的microtubules大多比較短)

    • Subepithelial deposits are uncommon since the cryoglobulins are too large to pass GBM

    Fingerprint pattern in mixed cryoglobulinemia

    Cryoglobulinemic GN

6.Lab#

  • 主要:RA factor(type II?), cryoglobulin, HBV titers, anti-HCV, HCV RNA, HIV, C3, C4, other AIR titers, IFE
    • 【必考臨床檢驗 SOP】Cryoglobulin 採檢規範(PMID 23838352):
      • 採血針筒與試管須預熱至 37°C, 採血後全程 37°C 恆溫運送並於 37°C 凝固離心(否則在分離前就先冷析出→偽陰性)
      • 取得血清後置 4°C 靜置至少 72 小時(至 7 天), 測其沉降比例即 Cryocrit
      • 偽性檢驗異常: 室溫下冷析出的沉澱物會被血液分析儀誤判 → 偽性白血球增多與偽性血小板增多 (pseudoleukocytosis / pseudothrombocytosis)
    • 小心有cryoglobulin的人很少一部分才有症狀[Ex:HCV(+)者50%有cryoglobulin(+), 但cryoglobulin(+)的HCV Pts只有1/3有S/S]
    • 有cryoglobulinemia S/S者未必可以測到有cryoglobulin(部分因為技術問題)
  • Tissue biopsy:leukocytoclastic vasculitis; occasionally cryoglobulins in BV lumen(→ 見上段採檢規範偽性血球異常)

7.D/D#

  • Other vasculitis/thromboembolism disease:HSP, ANCA, AIR, APS, TMA, Rickettsia, Malaria(本來就可以MPGN, cryoglobulinemia, MGN), Babesiosis, atrial myxoma...

8.Tx#

  • Cold avoidance and analgesics
  • Type I
    • Tx of underlying
  • Type II-III
    • If idiopathic
      • If mild to moderate manifestation
        • Colchicine(1-2mg/day) or low dose steroid(10-25mg/day, taper to <10mg/day by 6M if feasible)
      • if severe(any):severe digital ischemia/vasculitis, RPGN/nephrotic syndrome, GI vasculitis, pulmonary vasculitis, CNS vasculitis, severe neuropathy, heart failure
        • Rituximab(alternative:Endoxan) + rapid tapered Steroid
          • 註:Rituximab打贏Endoxan
          • Add plasmapheresis (if life threatening or hyperviscosity syndrome)
    • If underlying(+)
      • If mild to moderate: 治療潛在病因即可(HCV 給予 DAA 抗病毒)
      • If severe: 治療潛在病因 + Rituximab(alternative:Endoxan) + rapid tapered Steroid ± plasmapheresis(若危及生命或高黏滯度)(HBV 先以 Entecavir 覆蓋、HIV 啟動 ART)
        • 【治療核心金句】HCV-cryo(KDIGO 2022; PMID 36411019): DAA 為治癒 HCV 冷凝球蛋白血症之第一線基石（典型臨床證據者啟動 DAA 前不再強制腎切片）；若合併重症/器官威脅（RPGN、nephrotic、下肢壞死潰瘍），應立即聯合 Rituximab + 短療程類固醇（± 危及生命時血漿置換）與 DAA。現代 DAA 無免疫刺激風險，不需像過去干擾素時代延後投藥。
    • 註:TPE/DFPP studies多用在MPGN, neuropathy, arthralgia, ulcerating purpura
      • Uptodate建議:hyperviscosity syndrome, crescent GN, intestinal vasculitis, pulmonary hemorrhage, severe/refractory skin ulcers者併用TPE/DFPP

反向連結

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