Pocket Medicine: The Massachusetts General Hospital Handbook of Internal Medicine (115 page)

Etiologies

• Infections (types II & III): viral (
HCV
, HBV, HIV, HAV, EBV, CMV), bacterial (endocarditis, strep, etc.), fungal (coccidiomycosis, etc.) and parasitic (malaria, amoebiasis) • Hematologic diseases

type I: MM, CLL, Waldenström’s

type II: B-cell lymphomas, solid organ malignancies

• Autoimmune syndromes (type III > II):
Sjögren’s syndrome
, SLE, RA, PAN

• Essential (idiopathic) in 10% of cases

• Renal transplant recipients (Clin Nephrol 2008;69:239)

Pathophysiology

• Chronic immune stimulation and/or lymphoproliferation → cryoglobulin generation • Type I: cryo precipitation in microcirculation →
hyperviscosity
&
vascular occlusion
• Types II/III: defective/insufficient immune complex (IC) clearance → IC-mediated inflammation of blood vessels w/ complement activation →
vasculitis
Clinical manifestations
(systemic sx usually due to type II
> III)

• Most patients with cryoglobulinemia are asx

• Type I: hyperviscosity (cold worsens sx) → H/A, visual disturbance, livedo, digital ischemia • Type II: vasculitis (sx not affected by cold exposure)

General:
weakness
, low-grade fever

Dermatologic (54–80%): lower extremity
purpura
, livedo reticularis, leg ulcers

Joint (44–70%): symmetric, migratory
arthralgias
of small or medium joints

Renal (50%):
glomerulonephritis
(proteinuria, hematuria, ARF, HTN, edema)

Neurologic (17–60%):
peripheral neuropathy
(polyneuropathy > mononeuritis multiplex)

Hematologic: anemia, thrombocytopenia, ↑ risk of B-cell lymphoma

GI (5%): abdominal pain, hepatosplenomegaly, abnormal LFTs

Diagnostic studies

• ✓ Cryoglobulins; must keep blood warmed to 37°C at all times en route to lab; early cooling causes false
cryoglobulin, loss of RF and ↓↓ complement • Cryocrit is quantification of cryoprotein, does not always correlate w/ disease activity • False ↑ in WBC or plt on automated CBC, due to cryoprecipitation

• Type I: ✓ serum viscosity, symptomatic if ≥4.0 centipoise; complement levels normal • Type II: ↓
C4 levels
, variable C3 levels, ↑ ESR,
rheumatoid factor (RF) ✓
HCV, HBV, & HIV serologies
in all Pts w/ mixed cryoglobulinemia Bx of affected tissue: hyaline thrombi; vasculitis w/ mixed inflammatory infiltrates of small vessels; leukocytoclastic vasculitis in purpuric lesions
Treatment
(Autoimmun Rev 2011;10:444; Arth Rheum 2012;64:604; Blood 2012;119:5996)
•
Treat underlying disorder
:

Lymphoproliferative disease: chemotherapy and/or radiation

HCV: antivirals ± immunosuppression for severe disease

Connective tissue-related disease: DMARD/steroids ± rituximab

• Type I: Plasma exchange if hyperviscosity

• Type II: NSAIDs for control of mild symptoms for Pts w/ normal renal function

Rituximab or cyclophosphamide for major organ involvement

Plasmapheresis or plasma exchange in severe, life-threatening disease

AMYLOIDOSIS

The deposition of misfolded and insoluble fibrous proteins in normal organs and tissues.

Diagnostic studies

• If suspect AL → ✓ SIEP & UIEP (↑ Se vs. SPEP & UPEP) & free light chains, ± BM bx • If suspect renal involvement ✓ U/A (proteinuria)

• If suspect cardiac involvement: ✓ ECG (↓ voltage, conduction abnl), echo (biventricular thickening with “granular sparkling” appearance; ↑ wall w/o ↑ volt 75% Se, 95% Sp), MRI • Biopsy (abdominal SC fat pad, rectal or affected tissue) → apple-green birefringence on
Congo red stain
; fat pad bx Se 60–85%, Sp 90–100%

• Genetic testing for hereditary forms

Treatment

• AL: ? high-dose melphalan → auto HSCT if limited organ dysfxn (NEJM 2007;357:1083); o/w low-dose melphalan + dexamethasone; novel agents (eg, bortezomib, lenalidomide, thalidomide) being evaluated (J Hematol Oncol 2011;4:47) • AA: Rx underlying disease; colchicine for FMF esp. to prevent progressive renal disease (NEJM 2007;356:23); eprodisate promising for renal disease (NEJM 2007;356:2349) • For hereditary amyloidoses in which amyloid precursor protein is produced by the

liver (eg, TTR), liver transplantation may prevent further deposition

• Cardiac involv.: diuretics; avoid dig & CCB; avoid vasodilators; ? ICD for 1° prevention • Heart, kidney and liver Tx may be considered in those w/ advanced disease
Prognosis

• AL amyloid: median survival ~12–18 mo; if cardiac involvement, median survival ~6 mo • AA amyloid: median survival ~11 y (NEJM 2007;356:2361)

CHANGE IN MENTAL STATUS

Definitions (description of patient & timing is most helpful)

•
Unresponsive
: implies ↓ arousal or ability to follow commands, specify w/ exam

•
Delirium
(aka acute confusional state or encephalopathy): acute change in attention and consciousness with fluctuations. May include sleep–wake dysregulation, autonomic changes, abnormal sensory perception and changes in affect as additional features.

•
Dementia:
impaired cognition, often incl. memory. Usually chronic & progressive, eventually encompassing more anatomical & functional parts of the nervous system.

Initial evaluation

•
History
(witness & background
crucial
): time course, previous illnesses including dementia or psych; head trauma; meds, drug/alcohol use; infection/immune status

•
General physical exam
:
vital signs
, signs of trauma, asterixis, stigmata of liver disease, embolic phenomena, signs of drug use, nuchal rigidity (may be present in meningitis or SAH, but
do not test
if possible trauma/cervical spine fracture)

•
Neurologic exam
(most meaningful off sedatives/paralytics): look for focality or s/s of ↑ ICP (eg, HA, vomiting, papilledema, unilateral dilated pupil, ↑ BP)