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A
53-year-old woman had been diagnosed as having chronic
hepatitis C infection for 10 years. She had been otherwise
healthy and received regular follow-up at this hospital. Three
months earlier before this admission, she started to
experience general fatigue and myalgia that were attributed to
over-exercise by herself. However, resting did not relieve
those symptoms. At the same time, her hepatic functions were
abnormal (Table 2).
Two weeks
later, she started to experience pain at both knees and
knuckles of both hands which she attributed to degeneration
joint disease. A month prior to the admission, she noticed
palpable, lace-like purplish discolorations on her lower legs.
There was no swelling or heat of the skin lesion.
Additionally, she suffered from mild exertional dyspnea and
noticed foamy urine and mild leg edema two weeks prior to the
admission. She sought medical attention at hepatology clinic
where both impaired hepatic and renal functions were noted
(Table 2). She was referred to nephrology clinic and was
admitted for further study of the impaired renal functions.
She denied taking any drug or had any injury of the legs
recently. She also denied any renal disease in the past. There
was no family history of renal disease or skin lesions.
On admission, she had clear
consciousness with acutely-ill appearance. Her blood pressure
was 144/88 mmHg, pulse rate was 89 beats per minute,
respiration rate was 24 breaths per minute, and temperature
was 36.8o
C. The pulse oximetry showed SpO2
96% while she was breathing ambient air. The conjunctiva was
pink and the sclera was mildly icteric. Lungs were
symmetrically expanded but with basal crackles. Examinations of
the heart and abdomen were normal.
There was pitting edema and palpable, erythematous to
purplish lace-like skin purpura at the lower extremities. The skin lesion was
not tender. No inflammation of the joints was noted although
she reported arthralgia of the proximal interphalangeal and metacarpophalangeal
joints, knees, and ankles.
On admission, further
deterioration of liver and renal functions was noted. Renal
sonography did not show post-renal cause of acute renal
failure and she was treated with intravenous diuretics for
fluid retention. Renal biopsy was performed and pathology of
the renal biopsy specimen showed findings of
membranoproliferative glomerulonephritis (MPGN), type I. Based
on the biopsy result, a history of chronic hepatitis C
infection and the presence of suspected vasculitis on the
lower extremities, the diagnosis of mixed essential
cryoglobulinemia-related acute renal failure was made. Because
of worsening renal functions, fluid retention and poor
response to the diuritics, hemodialysis and plasmapheresis
were initiated. Treatment with interferon-alpha and ribavirin
for hepatitis C infection was also initiated but pulsed
steroid therapy for acute nephritis was not prescribed due to
the concerns of side effects. Her renal function improved
gradually with adequate urine output and hemodialysis and
plasmapheresis were discontinued. During hospitalization, her
liver functions also improved gradually. However, her renal
function can not reach the normal level as in the past (Table 2). After her general condition was stable, she was discharged
and followed up at the hepatology clinic to continue
interferon and ribavirin therapy.
Results of laboratory tests and radiography
Table 1.
CBC and differential count
|
Date |
WBC
K/μL |
Hgb
g/dL |
Hct
(%) |
Plt
(K/μL) |
Band
(%) |
Seg
(%) |
Eos
(%) |
Lym
(%) |
|
3 months prior to the admission |
9.68 |
11.3 |
33.5 |
170 |
0 |
88 |
0.2 |
2.5 |
|
2 weeks prior to the admission |
9.63 |
10.6 |
30.1 |
175 |
N/A |
N/A |
N/A |
N/A |
|
Hospitalization
day
1 |
10.56 |
9.6 |
28.5 |
165 |
0 |
89 |
2.6 |
2.5 |
|
day 3 |
10.48 |
10.8 |
32.4 |
155 |
N/A |
N/A |
N/A |
N/A |
|
day 7 |
9.33 |
10.8 |
32.7 |
160 |
N/A |
N/A |
N/A |
N/A |
|
day 10 |
9.30 |
11.0 |
33.1 |
156 |
N/A |
N/A |
N/A |
N/A |
|
day 15 |
9.43 |
11.3 |
33.4 |
160 |
N/A |
N/A |
N/A |
N/A |
|
day 18 |
9.40 |
11.2 |
33.2 |
160 |
N/A |
N/A |
N/A |
N/A |
Table 2. Biochemistry
|
Date |
BUN
(mg/dl) |
Cre
(mg/dl) |
Na
(mmol/l) |
K
(mmol/l) |
AST
(U/l) |
ALT
(U/l) |
Bil (T)
mg/dL
|
|
3 months prior to the admission |
22 |
1.3 |
138 |
4.8 |
65 |
75 |
1.0 |
|
2 weeks prior to the admission |
50 |
3.3 |
135 |
4.6 |
185 |
200 |
N/A |
|
Hospitalization
day
1 |
83 |
7.2 |
133 |
4.6 |
420 |
440 |
1.8 |
|
day 3 |
87 |
7.6 |
132 |
4.7 |
450 |
512 |
2.0 |
|
day 7 |
95 |
8.3 |
134 |
4.5 |
490 |
526 |
1.8 |
|
day 10 |
65 |
5.3 |
136 |
4.3 |
495 |
524 |
1.7 |
|
day 15 |
45 |
4.3 |
135 |
4.4 |
440 |
480 |
N/A |
|
day 18 |
43 |
4.1 |
137 |
4.3 |
420 |
465 |
1.4 |
|
day 21 |
42 |
3.9 |
137 |
4.2 |
380 |
435 |
1.3 |
Table 3. Urine analysis
|
Date |
Appearance |
Specific
gravity
|
pH |
Protein
(mg/dl) |
Glucose |
Ketone |
Occult
blood
|
|
2 weeks prior to the admission |
yellowish, clear |
1.010 |
6.5 |
>300 |
-- |
-- |
1+ |
|
Hospitalization
day
1 |
yellowish, clear |
1.013 |
6.5 |
>300 |
-- |
-- |
3+ |
|
day 15 |
yellowish, clear |
1.011 |
6.8 |
>300 |
-- |
-- |
2+ |
|
Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial cells
|
Cast |
Bacteria |
|
2 weeks prior to the admission |
0.1 |
1+ |
5-10 |
15-20 |
1-3 |
Granular |
-- |
|
Hospitalization day
1 |
0.1 |
2+ |
>100 |
12-15 |
1-3 |
Granular |
-- |
|
day 15 |
0.1 |
1+ |
10-20 |
15-20 |
1-3 |
Granular |
-- |
4. Autoimmune
profiles:
C3: 69.4 (normal, 81.61-181.41), C4:
<6.7 (normal, 16.73-38.17)
C-ANCA & P-ANCA:
negative
Anti-HCV antibody: positive
Cryoglobulin:
positive
5. CXR: Mildly enlarged heart size and
bilateral costo-pleural angles blunting
6. Renal sonography: Normal kidney size. Parenchymal renal
disease, bilateral. No evidence of
hydronephrosis.
< 病例分析
>
冷凝球蛋白(Cryoglobulin)是人類血液中的一群在低溫(或室溫)會沈澱，但在體溫或高溫下則會再溶解的一種免疫球蛋白。臨床上主要可分為三型，第一型是由單株免疫球蛋白(single
monoclonal
immunoglobulin)所組成，通常發生在血液方面的疾病。第二型及第三型都是混合型免疫球蛋白（mixed
cryoglobulins）。第二型及第三型的差別在於第二型是由單株免疫球蛋白(monoclonal
IgM)組成，而第三型則是由多株免疫球蛋白(polyclonal
IgM)組成。不過，第二型及第三型都具有類風濕因子活性(rheumatoid factor
activity)，而可以與多株免疫球蛋白(polyclonal immunoglobulin)結合。Mixed
cryoglobulinemia syndrome是經由免疫複合體(immune
complex)而引起的一連串免疫反應造成的血管炎，即是第二型及第三型cryoglobulinemia所引起。臨床上第一型約佔10至15%，第二型約佔50至60%，所以臨床上常見的以mixed
cryoglobulinemia為主。第一型極少造成血管炎相關的症狀，反以周邊血管阻塞為主—即以hyperviscosity表現，如purpura、acrocyanosis、Raynaud
phenomena、ulcers或gangrene。第一型cryoglobulinemia常與lymphoproliferative
diseases相關，臨床上有時與Waldenstrom's macroglobulinemia、multiple
myeloma、immunocytoma或chronic lymphocytic leukaemia難以區分。而mixed
cryoglobulinemia
syndrome臨床上的triads為purpura、weakness及arthralgias，且許多器官都會被侵犯，尤其是因為中小型血管發炎引起的腎臟
(membranoproliferative glomerulonephritis)及周邊神經系統病變(peripheral
neuropathy)。疾病初期，病患可以只有cryoglobulinemia但沒有症狀，直到完整的mixed
cryoglobulinemia syndrome表現。甚至病患也可有mixed cryoglobulinemia
syndrome的表現但卻沒有cryoglobulinemia，因此要重複檢驗，這也可排除偽陰性的可能。Purpura是mixed
cryoglobulinemia
syndrome主要的表現，大約55到100%的第二型及第三型cryoglobulinemia病患會出現。Cryoglobulinemic
purpura 通常是間歇性且可被觸摸到的，多出現在下肢，但偶爾也在臀部及軀幹出現。約三分之ㄧ的mixed
cryoglobulinemia病患會有腎臟侵犯，這也是mixed
cryoglobulinemia病患的主要死因。腎臟侵犯多在
purpura,出現之後發生，但也有同時出現的。診斷時常見的表現為proteinuria、microscopic
hematuria及高血壓並伴有中等程度的腎功能障礙。20%的病患的腎臟侵犯以nephrotic
syndrome表現，另20至30%則以急性腎炎(microscopic或macroscopic
hematuria、proteinuria及腎功能急速惡化)表現。80%的腎臟病理最常見的表現為type I
membranoproliferative glomerulonephritis。
Mixed
cryoglobulinemia syndrome 可以是由感染或全身性疾病所引起 (Table
4)
，但在此將只討論與hepatitis C virus
(HCV)相關部分。遠自西元1990年的研究就已知道HCV可能是引起這種疾病的主要誘發因子，而mixed
cryoglobulinemia syndrome和HCV 感染之間的關係與病毒長期刺激B-cell的polyclonal
proliferation有關。在essential MC
syndrome的病患中，其HCV感染的盛行率可從30%到96%不等。反過來說，
20到56%帶有HCV的病患會表現cryoglobulinemia，可是這些病患中也只有10到27%會有cryoglobulinemia的臨床相關表現。與HCV相關的cryoglobulinemia，其沉澱物包含了大部分的病毒抗原、相關抗體及HCV的RNA。因此這些直接或間接的支持了HCV及cryoglobulinemia的關係。在台灣的essential
MC syndrome的病患中，最常見的病因即為HCV感染。
在治療cryoglobulinemia時要知道的是並沒有任何生物指標和疾病的活性有相關。而一般的治療原則為：無症狀的病患並不需要治療，而有症狀的病患則需根據症狀的嚴重程度及既有疾病考慮。當HCV感染的病患出現mixed
cryoglobulinemia syndrome的症狀時，治療的方針就必要考慮包括病毒的清除。因HCV感染引發之mixed
cryoglobulinemia，單獨以干擾素(interferon)或合併ribavirin是標準治療。有許多的報告指出，干擾素治療可在60至100%的HCV感染相關的mixed
cryoglobulinemia病患身上達到臨床上有意義的改善，而此效果主要來自對HCV的抑制作用，但即使症狀改善，cryoglobulin仍然還是會呈現陽性反應。一般來說，臨床上以purpuric
lesion改善最快，而neuropathy及nephropathy則最慢。至於ribavirin在與interferon合併使用時，也有療效。而新一代的pegylated
interferon合併ribavirin使用也有不錯的效果。至於plasmapheresisis對mixed
cryoglobulinemia治療的效果則來自對免疫複合體、抗體及一些有毒物質的移除，不過這只具有短期緩解效果。
References
- Postgrad Med J. 2007 Feb;83(976):87-94
- Blood Rev. 2007 Jul;21(4):183-200.
- Cryoglobulinemia: eMedicine Rheumatology.
(emedicine.medscape.com)
- Comprehensive Clinical Nephrology 2nd
edition
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Case Discussion
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