918 Part Seven Organ-Specific Inflammatory Disease
FIG 68.1 Red Blood Cell Cast. Cast present in situ within the
lumen of a distal renal tubule. (Periodic acid–Schiff [PAS] stain.)
FIG 68.3 Normal Glomerular Architecture. The glomerular
capillary loops are patent and have normal thickness. Neither
increased endocapillary cells nor expanded mesangial matrix
encroach upon the patency of the capillary lumina. (Periodic
acid–Schiff [PAS] stain).
TABLE 68.1 Indications for renal Biopsy
1. Active “nephritic” urine sediment
• Dysmorphic erythrocytes: >10 per high-power field
• Cellular casts: erythrocyte or leukocyte
2. Proteinuria >2 g/day
3. Abnormal renal function
• Associated with the above features of active nephritis
• Particularly important if the duration of renal disease and/or rate
of change are unknown
63( ,J* ,J$ ,J0 κ λ 4. Document indications for use of high-risk therapeutic interventions
FIG 68.2 Immunofixation Electrophoresis of Urinary Protein.
Proteins in a concentrated urine protein are separated in six
replicate lanes by standard protein electrophoresis. Separated clarify the precise type of renal involvement, to formulate a
proteins are identified by overlaying specific antisera to immu- prognosis, and to direct therapy. Some of the more important
noglobulin G (IgG), IgA, IgM, κ and λ. In this example, a indications for renal biopsy are listed in Table 68.1. Light
monoclonal paraprotein composed of λlight chain is identified microscopy appearance of a normal glomerulus is illustrated in
as an intense narrow band in the far right hand lane. Fig. 68.3.
ACUTE NEPHRITIC SYNDROME MINIMAL CHANGE DISEASE
Acute nephritic syndrome is characterized by hematuria (dys-
morphic cells), erythrocyte casts, abnormal proteinuria, fluid KeY COnCePtS
retention, azotemia, and hypertension. Histologically, this constel- Minimal Change Nephropathy
lation of clinical findings is due to proliferative glomerulonephritis.
A variant of this syndrome, called rapidly progressive glomeru- • Most common cause of nephrotic syndrome in children
• High rate of response to glucocorticoids
lonephritis (RPGN), is defined by ≥50% loss of glomerular filtra- • Cyclophosphamide is useful for frequent relapsers
tion rate over 3 months, along with characteristically >50% of • Renal prognosis is characteristically excellent
glomeruli showing cellular crescents on renal biopsy.. • Subset may evolve to focal segmental glomerulosclerosis
CHRONIC GLOMERULONEPHRITIS Nephrotic syndrome of childhood is mainly caused by minimal
change disease (MCD). The frequency of MCD in adults with
Broad and waxy casts are features of chronic renal disease that nephrotic syndrome is low compared with those of other entities
are not likely to be seen in acute or subacute glomerulonephritis. discussed below. 4
Clinical Features
RENAL BIOPSY
Minimal change nephropathy characteristically presents with a
After extensive clinical and laboratory evaluations, renal biopsy rather precipitous onset of severe nephrotic syndrome in the
may be indicated to establish or confirm a tissue diagnosis, to absence of signs of a systemic disease. There are no specific tests
CHaPter 68 Immunological Renal Diseases 919
other than kidney biopsy to establish a diagnosis of minimal KeY COnCePtS
change nephropathy, although proteinuria exclusively comprising
albumin is characteristic; standard immunological screening tests Focal Segmental Glomerulosclerosis
are usually normal. • Nephrotic syndrome with progressive renal insufficiency
• Glomerular permeability factor in plasma of some cases
Etiology and Pathogenesis • Unpredictable responses to glucocorticoids or cyclophosphamide
The cause of MCD is largely unknown. There is evidence of • Cyclosporine effective, but relapses common upon withdrawal
immune dysregulation, mainly involving cell-mediated immunity, • Moderately high relapse rate in renal allografts
which is supported by the tendency of the disease to manifest
and relapse after viral infections or an allergic reaction, the
association of some cases with Hodgkin lymphoma, and its a poorer response to immunosuppressive drug therapies, and a
characteristically favorable response to immunosuppressive drugs. higher risk of progression to end-stage renal failure. The incidence
Another hypothesis is that a systemic circulating factor of immune of FSGS is clearly increasing as a cause of nephrotic syndrome,
5
origin results in increased glomerular permeability (discussed particularly among black patients.
in the section on “Focal Segmental Glomerulosclerosis”)
The basic lesion of MCD is loss or neutralization of the normal Etiology and Pathogenesis
high density of anionic proteoglycans in the glomerular capillary Diverse etiologies may disrupt the podocyte structure and function
loops. Dissipation of the negative-charge barrier allows anion- leading to the histological expression of FSGS. Genetic mutations
charged albumin to pass freely. Interdigitating foot processes of key podocyte proteins, such as podocin and nephrin play a
normally joined by intercellular bridges, called slit diaphragms, role in a subset of FSGS that occurs in children or young adults.
form a second barrier to the passage of protein into the urinary Circulating permeability factors have been proposed as mediators
space. Characteristically, the podocyte foot processes and slit of podocyte injury in FSGS (i.e., soluble urokinase-type plas-
diaphragms are also disrupted in minimal change nephropathy. minogen activator receptor). In certain situations, it appears
that podocytes have increased surface expression of the trans-
Pathology membrane protein B7-1 (CD80) that stimulates interactions with
7
With the use of light microscopy, renal biopsy results are found T cells and leads to foot process effacement. “Secondary” forms
to be essentially normal. Electron microscopy shows the char- of FSGS may result from toxic effects of drugs (i.e., pamidronate),
acteristic pathological lesion, where there is fusion of the foot viral infections (e.g., human immunodeficiency virus [HIV]) or
processes of the epithelial cells (podocytes) diffusely around maladaptive hemodynamic stress (i.e., resulting from obesity or
glomerular capillaries. reduced nephron mass).
Treatment Pathology
MCD is characteristically exquisitely sensitive to glucocorticoids The characteristic renal pathology includes segmental areas of
(remitting within the first few weeks of therapy in >90% of podocyte damage and detachment, irregular foot process fusion,
children). The response rate to glucocorticoids in adults is and collapse of glomerular capillaries associated with marked
somewhat lower and more delayed. A substantial portion of local increase in matrix and collagen accumulation. Segmental
patients with minimal change nephropathy face long-term dif- sclerotic areas typically stain nonspecifically with antisera to
ficulties because of the disease and the therapy: Some are IgM and C3 (but not to IgG or IgA), particularly in areas of
steroid-resistant from the start; others are steroid-dependent for glomerular tuft hyalinosis (representing trapped plasma con-
control of nephrotic syndrome; still others become frequent stituents), but none of these collections should be considered
relapsers and suffer substantial steroid toxicity with repeated to represent classic immune complexes. Various histological
treatments. Controlled trials have shown that alkylating agents subtypes of FSGS have been described on the basis of the type
(i.e., cyclophosphamide) increase response rates and reduce rates and location of lesions. One classification scheme divides FSGS
of relapse. Cyclosporine (CSA) and tacrolimus are alternatives into five variants: tip, perihilar, cellular, collapsing, and not
8
to prolonged and repeated courses of steroid therapy, but relapses otherwise specified (NOS) (Fig. 68.4). The collapsing variant
frequently occur with drug withdrawal. Rituximab (a monoclonal of FSGS, which has been associated with viral infections, notably
antibody [mAb] to CD20 on B cells) has been used with variable HIV, tends to follow a particularly aggressive course.
success, particularly in those who are steroid-dependent or
frequent relapsers. Also, rituximab may have “off target” effects Treatment
on the podocyte cytoskeletal structure. 6 Patients with primary FSGS generally have hypoalbuminemia
The risk of progression to end-stage renal failure is extremely and nephrotic range proteinuria, whereas those with secondary
low in true MCD. Renal biopsy sampling errors account for a FSGS typically have subnephrotic proteinuria, a normal or near
mistaken diagnosis of MCD in a proportion of cases that are, normal serum albumin concentration, no peripheral edema, and
in fact, focal segmental glomerulosclerosis (FSGS). It is debated focal rather than diffuse foot process effacement on kidney biopsy.
whether MCD and FSGS represent different manifestations of The possibility of genetic forms of FSGS should be considered
one disease (with MCD potentially progressing to FSGS), or if before beginning immunosuppressive therapy, but steroid
they represent two different diseases. resistance may also serve as a clue to genetic forms of FSGS.
Treatment of genetic and hyperfiltration-induced forms of
FOCAL SEGMENTAL GLOMERULOSCLEROSIS FSGS is focused mostly on renoprotection with angiotensin
antagonists and lipid-lowering agents (statins). The treatment
Patients with FSGS have a higher frequency of microscopic of other forms of primary FSGS is basically similar to that of
hematuria, higher frequency of persistent nephrotic syndrome, MCD and includes immunosuppression with prednisone,
920 Part Seven Organ-Specific Inflammatory Disease
$ %
& '
FIG 68.4 Focal Segmental Glomerulosclerosis (FSGS). Several forms of glomerular lesions
are seen in FSGS, often within the same biopsy: A, minimal abnormality (periodic acid–Schiff
[PAS] stain); B, tip lesion manifested by segmental glomerular tuft lesion near the origin of the
proximal tubule (PAS stain); C, classical perihilar lesion (PAS stain); and D, collapsing glomerulopathy;
the glomerulus is globally contracted with wrinkling of the basement membranes; this is associated
with hyperplasia of podocytes surrounding the glomerular capillaries (methenamine silver stain).
cyclophosphamide, calcineurin inhibitors, or mycophenolate. KeY COnCePtS
There are mixed outcomes with use of rituximab for FSGS, but
it appears less effective for steroid resistant cases. 9,10 Complete Membranous Nephropathy (MN)
remission of proteinuria is less commonly achieved in FSGS • Common cause of idiopathic nephrotic syndrome in adults
than in MCD. Relapses of the disease and progression to end-stage • Autoantibodies to phospholipase A 2 receptor (PLA 2 R) detected in large
kidney disease (ESKD) remains a major concern despite immu- percentage of patients with primary MN
nosuppression, particularly in steroid-resistant and frequently • Several secondary causes: systemic lupus erythematosus (SLE), drugs,
relapsing patients. Several novel therapies that target various chronic hepatitis, certain malignancies
immunological, inflammatory, and costimulatory pathways (i.e., • One-quarter of patients have spontaneous remission
blockade of CD 80 with cytotoxic T lymphocyte antigen 4-Ig • One-quarter of patients develop end-stage renal disease within a
decade
(CTLA-4-Ig) are currently under investigation for FSGS. 11,12 • Protracted nephrotic syndrome confers risks of cardiovascular and
thromboembolic events
MEMBRANOUS NEPHROPATHY • Therapies: steroids, alkylating agents, calcineurin inhibitors, rituximab,
lipid-lowering drugs, angiotensin antagonists
MN is identified in approximately 20% of adults who undergo
renal biopsy for nephrotic syndrome. It is a less frequent cause
of nephrotic syndrome in children. Primary MN is usually a Etiology and Pathogenesis
diagnosis of exclusion after considering secondary causes, such MN is characterized by subepithelial (epimembranous) immune
as medication reactions, infections, neoplasms, and systemic deposits containing IgG and complement components. The
illnesses (i.e., SLE) leading hypothesis based on experimental models is that immune
CHaPter 68 Immunological Renal Diseases 921
$
FIG 68.5 Membranous Nephropathy. Capillary walls are nearly
uniformly thickened but remain widely patent. Cellularity of the
glomerulus is normal (Periodic acid–Schiff [PAS] stain).
complexes are formed in situ by the interaction of a pathogenic
antibody with a constitutive glomerular antigen or with an antigen
that had been ectopically planted in the glomerulus. Major
advances have been made with the identification of several
constitutive podocyte surface antigens, which are the target of
autoantibodies in some subsets of patients with primary MN. 13,14
The majority (70-80%) of patients with primary MN have
circulating autoantibodies to M-type phospholipase A2 receptor
(PLA 2 R), a transmembrane receptor that is expressed in glo-
13
merular podocytes. Antibodies to thrombospondin type-1
domain containing 7A protein (THSDA7A) and neutral endo-
peptidase have been identified in smaller subsets of patients. 14
Clinicopathological Features
Patients with MN characteristically present with nephrotic syn-
drome. Renal biopsy is usually required to establish the diagnosis, %
although serological testing for relevant autoantibodies (i.e.,
anti–PLA 2 R) may be informative if renal biopsy is contraindicated. FIG 68.6 Membranous Nephropathy (Ultrastructure). A, Electron
In most cases, light microscopy shows uniform thickening micrograph demonstrates heavy, dark-staining immune complex
of the glomerular capillary walls without endocapillary cell deposits along the outer surface of the glomerular basement
proliferation (Fig. 68.5). Characteristic subepithelial (epimem- membrane and beneath the epithelial foot processes (hence
branous) and/or intramembranous deposits are seen on electron the terms subepithelial or epimembranous deposits). Note
microscopy (Fig. 68.6). Identification of PLA 2 R in glomerular the thickening and projections of the gray-staining basement
immune deposits (by immunofluorescence or immunohisto- membrane between the electron-dense deposits. B, Ultrastructure
chemistry) favors the diagnosis of primary MN; mesangial of a normal glomerular capillary wall for comparison.
deposits are often present in secondary MN. But a diagnosis of
secondary MN depends on concurrent abnormalities in clinical
and laboratory data.
is a relatively strong predictor of an adverse renal outcome. Some
Natural History studies suggest that the titer of autoantibody to PLA 2 R at baseline
The clinical course of primary MN is highly variable. On average, correlates with disease activity such that higher titers may be
about one-quarter of adult patients progress to ESKD within associated with greater risk of renal function decline, whereas
10 years. Another quarter experiences a spontaneous remission low titers may be associated with greater probability of spontane-
of proteinuria. The majority is likely to have persistent proteinuria ous remission. 15
and moderately impaired renal function over an extended period
of observation. Treatment
Baseline characteristics, such as severe nephrotic syndrome, Management of patients with MN usually includes diuretics to
hypertension, and azotemia, have been associated with poor reduce edema, lipid-lowering drugs (for severe hyperlipidemia),
outcomes. Protracted high-grade nephrotic-range proteinuria anticoagulant therapy for thromboembolic complications, and
922 Part Seven Organ-Specific Inflammatory Disease
FIG 68.7 Membranoproliferative Glomerulonephritis (MPGN). Glomerulus exhibits the typical
lobulated appearance of this disease. Markedly increased mesangial cells and matrix in all of the
lobules. Mesangium extends outward into the capillary loops and forms double contours with
the glomerular basement membrane. (Periodic acid–Schiff [PAS] stain).
antihypertensive agents. Angiotensin antagonists have been shown pattern of injury is characterized by mesangial matrix expansion
to have a substantial antiproteinuric effect. Immunosuppres- and increased cellularity and thickening of the glomerular capillary
sive treatment is generally reserved for patients with persistent walls with a double contour appearance. These changes give a
high-grade proteinuria (>4 g/day. First-line immunosuppressive lobulated appearance to the glomerulus (Fig. 68.7).
therapy consists of cytotoxic drugs (usually cyclophosphamide)
in combination with glucocorticoids or a calcineurin inhibitor Etiology and Pathogenesis
16
(CSA or tacrolimus) with or without low-dose glucocorticoids. Until recently MPGN was classified into three types based on
The most compelling results from controlled trials have shown the location and type of electron dense deposits: type 1 character-
that patients with MN treated with alternating monthly courses of ized by subendothelial deposits; type II by intramembranous
pulse methylprednisolone and chlorambucil or cyclophosphamide electron dense deposits in a ribbon-like pattern (also referred
were more likely to experience a remission of the nephrotic to as dense deposit disease [DDD]); and type III by subendothelial
syndrome and achieve stable renal function compared with and subepithelial deposits (Fig. 68.8). This older classification
controls. Rituximab may be a useful alternative for treatment scheme also made a distinction between secondary causes when
of MN based on encouraging results from pilot studies and a it was possible to identify an etiology
good safety profile compared with other immunosuppressive New insight into the pathogenesis of MPGN has recently led
regimens. 16–19 to a major paradigm shift in the classification of this disease. Of
great importance is the recognition that some cases of MPGN
MEMBRANOPROLIFERATIVE result from the deposition of Igs with secondary complement
GLOMERULONEPHRITIS activation, whereas others arise from primary abnormalities in
20
the control of complement activation. The new classification
KeY COnCePtS system now broadly categorizes MPGN into Ig-mediated or
complement-mediated disease based on the pattern and composi-
Membranoproliferative Glomerulonephritis tion of the deposits, as assessed by immunofluorescence staining.
(MPGN) The presence of both Ig and complement (C3) indicates an
Ig-mediated process in which immune complexes are deposited
• Histologically classified into immune complex–mediated glomerulo- and then secondarily activate the classical complement pathway.
nephritis or complement-mediated glomerulonephritis based on
immunofluorescence staining pattern In contrast, the presence of complement staining (C3) without
• C3 glomerulopathy characterized by C3 accumulation in the glomeruli significant Ig deposition implies that an antibody-independent
in the form of electron-dense deposits. means of complement activation has been triggered and suggests
• Genetic or acquired abnormalities in the activation of the alternate a primary problem with regulation of the alternative complement
alternative complement pathway complement pathway associated pathway (Fig. 68.9). Such diseases are now grouped under the
with C3 glomerulopathy umbrella term, “C3 glomerulopathy” (C3G), which encompasses
• Response to immunosuppressive drug treatment generally poor both C3 glomerulonephritis (C3GN) and DDD. A diagnosis
21
• Tends to recur in renal allografts
of C3G should prompt an evaluation for inherited mutations
of complement regulatory proteins (i.e., factor H or factor I) or
Membranoproliferative glomerulonephritis (MPGN) is a morpho- acquired autoantibodies to regulatory proteins (i.e., C3 nephritic
logical entity that encompasses a heterogeneous group of diseases factor or anti-factor H), which lead to dysregulation of the
with a similar appearance at the light microscopic level. The alternative pathway. C3 nephritic factor, an autoantibody to C3
CHaPter 68 Immunological Renal Diseases 923
$ %
FIG 68.8 Membranoproliferative Glomerulonephritis (MPGN) Ultrastructure. A, Capillary wall
is markedly thickened and contains heavy, dark-staining, electron-dense immune complexes in
the subendothelial space. Mesangium (lighter material) extends into the capillary loop, where
it is interposed between the basement membrane and the endothelium; the process gives the
appearance of a massively thickened capillary loop on hematoxylin and eosin (H&E) staining, and
the split appearance by periodic acid–Schiff (PAS) and silver stains. B, Dense deposit disease;
capillary loops contain smooth, continuous, linear dense material within the basement membrane.
convertase, is frequently detected in C3G. C3 nephritic factor is variable with up to 30% of patients progressing to ESKD.
stabilizes the convertase, rendering it resistant to control by factor The prognosis of DDD is worse, with almost half the patients
H, thus leading to persistent C3 activation and deposition of progressing to kidney failure. Idiopathic MPGN and MPGN
alternative pathway activation products in glomeruli. resulting from complement dysregulation tend to recur in renal
allografts; recurrences of both types of MPGN have a detrimental
Pathology effect on graft survival.
In addition to endocapillary proliferation and findings on
immunofluorescence, a double contour appearance to the glo- Treatment
merular basement membrane (GBM) best seen with silver stain It is important to recognize that existing treatment trials for
represents synthesis of GBM-like material from capillary wall MPGN predate the new classification system and our appreciation
remodeling. Irregular capillary wall subendothelial and mesangial of the different pathogenesis. Thus their relevance is questionable
deposits are seen by electron microscopy in Ig- mediated MPGN; because of the heterogeneity of patient populations. It is antici-
often small intramembranous and subepithelial deposits are also pated that the new diagnostic categories will better define groups
present in C3GN. The hallmark of C3GN is dominant bright of patients with similar pathogenesis, thus enabling a more
staining for C3 by immunofluorescence in the mesangium and rational approach to targeted therapy in the future.
glomerular capillary walls (see Fig. 68.9). There is no consensus regarding treatment of “idiopathic”
Double contours of the GBM are also present in conditions immune complex–mediated MPGN, but various immunosup-
associated with chronic endothelial injury, including thrombotic pressants have been used with variable success, including
microangiopathy, transplant glomerulopathy, and preeclampsia, prednisone alone or in combination with either mycophenolate
and show a histological appearance of MPGN by light microscopy. or cyclophosphamide. There are limited data on the role of
However, there are no associated immune deposits and immu- rituximab in this disease.
nofluorescence is negative for Ig and C3. Optimal treatment of C3GN remains unclear but will likely
need to be individualized on the basis of proper identification
Clinical Presentation of the defect in the alternative complement system (i.e., genetic
Although it is characteristically a chronic low-grade nephropathy, vs acquired autoantibodies). Chronic infusions of fresh frozen
some patients experience nephrotic syndrome and even rapidly plasma to replace missing complement factors may be beneficial in
progressive and crescentic disease. Hypocomplementemia is some cases. Immunosuppression with corticosteroids, rituximab,
common in all types of MPGN. In immune complex-mediated and mycophenolate is of theoretic benefit in cases resulting from
MPGN, serum C4 levels are characteristically low, consistent with pathogenic antibodies to complement regulatory proteins but
classical pathway activation. Serum C3 concentration may be is unproven. A more targeted approach using eculizumab,
normal or mildly decreased. In complement-mediated MPGN, a mAb that blocks activation of C5 complement (C5b-9),
serum C4 levels are normal, and C3 is typically low, consistent with has been tested in small series, but the data are inconclusive.
alternative pathway activation, but a normal serum C3 does not Additional new complement blocking agents may also hold
exclude the diagnosis. The renal outcome in C3 glomerulopathy promise. 22
924 Part Seven Organ-Specific Inflammatory Disease
$ &
% '
FIG 68.9 C3 Glomerulopathy. A, Glomerulus exhibiting the characteristic membranoproliferative
pattern (hematoxylin and eosin [H&E] stain). B, Immunofluorescence showing prominent glomerular
staining for C3 complement. C and D, Electron microscopy ultrastructure showing mesangial
interposition giving a double contour of the glomerular capillary wall, as well as interposed electron
dense deposits in the subendothelial space and the mesangium.
POSTINFECTIOUS NEPHROPATHIES entacavir, adefovir, tenofovir, and telbivudine. Treatment with
nucleoside/nucleotide analogues are generally used for at least
An ever-expanding list of infectious agents has been implicated 1 year and continued for at least 6 months after HBeAg sero-
in the pathogenesis of certain forms of immune-mediated conversion. Immunosuppression (corticosteroids with or without
nephropathies. cyclophosphamide or rituximab) may cautiously be considered
in patients with rapidly progressive glomerulonephritis, but
Viral Infections concomitant antiviral therapy is required.
Hepatitis B
Hepatitis B–associated nephropathy most frequently presents as Hepatitis C
nephrotic syndrome accompanied by microscopic hematuria; Hepatitis C virus (HCV) is a major cause of both transfusion-
renal biopsy most commonly shows MN. Immunofluorescence associated and sporadic chronic hepatitis. The most common
studies usually show Ig, C3, and some IgM staining in the HCV-associated renal disease is usually, but not invariably, MPGN
subepithelial region along the glomerular basement membranes in the context of type II mixed cryoglobulinemia. The pathogenesis
and in some cases viral antigens can be detected within the of the renal disease is caused by deposition within glomeruli of
glomerulus. Electron microscopy shows subepithelial and immune complexes containing HCV, anti-HCV antibody and
intramembranous deposits, but there may also be mesangial and virus-related (or unrelated) cryoglobulins.
even some subendothelial deposits. Treatment of HCV infection has greatly improved in the last
Therapy for hepatitis B renal disease has focused on antiviral few years. Historically, treatment was mainly based on IFN-α and
drugs because glucocorticoids and cytotoxic agents may promote ribavirin. These agents are now being replaced by HCV-specific
viral replication. Treatment generally consists of interferon-α antiviral drugs that are used in combination (i.e., sofosbuvir plus
23
(IFN-α) or nucleoside/nucleotide analogues, such as lamividine, ledipasvir), which are highly effective and often curative. The
CHaPter 68 Immunological Renal Diseases 925
evidence for antiviral treatment in HCV-related kidney disease KeY COnCePtS
is based mostly on IFN-based regimens, which have reported
remission of proteinuria and hematuria and improvement of Infection-Related Nephropathies
renal function. 24,25 There are limited data regarding use of the • Viral: Hepatitis B—membranous nephropathy; hepatitis C—cryoglobu-
newer antiviral agents in HCV-associated glomerulonephritis, but linemic membranoproliferative glomerulonephritis; human immuno-
26
these hold considerable promise. For patients with progressive deficiency virus (HIV)—focal segmental glomerulosclerosis (HIV
renal disease and/or nephrotic-range proteinuria, treatment with nephropathy)
rituximab or pulse intravenous steroids and cyclophosphamide • Bacterial (mainly gram-positive): Nephritogenic streptococcal infections,
may be warranted in conjunction with antiviral therapy. Treatment prosthetic device (shunt) infections, subacute bacterial endocarditis,
chronic deep tissue abscesses—mainly diffuse or focal proliferative
with rituximab and plasma exchange may provide additional glomerulonephritis
benefit in patients with HCV-associated severe cryoglobulinemia
refractory to antiviral therapy. 27,28
Human Immunodeficiency Virus
HIV-associated nephropathy (HIVAN), the first kidney disease or minimally depressed C4 levels, indicating activation of the
to be associated with HIV infection, is a collapsing form of focal alternative complement pathway.
segmental glomerulosclerosis accompanied by associated tubular Proliferative glomerulonephritis with polymorphonuclear
microcysts and interstitial inflammation. It was first described leukocyte and monocyte infiltration, granular immune deposits
in patients with acquired immune deficiency syndrome (AIDS) of IgG and C3, and dome-shaped electron-dense subepithelial
but also is occasionally diagnosed in less advanced cases of HIV deposits (humps) are characteristic. The prognosis is excellent
infection and before acute HIV seroconversion has been identified. in children; with supportive care, almost all will recover. Progres-
HIVAN classically presents with significant proteinuria and rapidly sive renal failure accompanied by severe hypertension appears
progressive kidney disease. HIVAN displays a striking racial to be more common in adults. Kidney biopsy is rarely needed
predilection for black patients, which may indicate the importance in the child but may be warranted if there is an atypical presenta-
of genetic influences. 29 tion or evolution. .
A spectrum of other renal abnormalities have also been The classic childhood form is still seen in developing countries
described in patients with HIV infection, including IgA but is now rare in developed countries. However, there has been
nephropathy, lupus-like glomerulonephritis, postinfectious an increase in the incidence of nonstreptococcal postinfectious
glomerulonephritis, MPGN, MN, cryoglobulinemic glomeru- glomerulonephritis or “infection-related” glomerulonephritis,
lonephritis, fibrillary and immunotactoid glomerulopathy, and which tends to be seen in older patients with multiple comorbidi-
thrombotic microangiopathy. 30,31 Tubulointerstitial changes ties, especially diabetes, HIV infection, and malignancy. These
related to drug toxicity, acute interstitial nephritis, or super- clinical variants are usually related to other infective agents, such
imposed viral, fungal, or mycobacterial infections may also be as Staphylococcus aureus, both methicillin-resistant (MRSA) and
present. methicillin-sensitive S. aureus, and may be characterized by an
The mainstay of treatment of HIVAN is combination anti- IgA-dominant glomerular immune complex deposition.
retroviral therapy (cART) regardless of the CD4 lymphocyte Etiology and pathogenesis. Glomerular injury results from
count. Highly effective modern therapies for HIV have reduced passive glomerular trapping of circulating immune complexes
the frequency of developing HIVAN and have greatly improved composed of nephritogenic bacterial antigens and IgG antibody
the otherwise dismal renal prognosis of HIVAN. This has greatly or by the in situ formation of immune complexes. This is fol-
improved the dismal renal prognosis of HIVAN. The evidence lowed by immune cell recruitment, production of chemical
for initiating cART in other HIV-associated immune complex mediators and cytokines, and local activation of the comple-
glomerular diseases is inconclusive, but use of cART is a rational ment and coagulation cascades that drive an inflammatory
approach. The use of standard immunosuppressive drugs in an response. 1
immunocompromised population is controversial. Current therapeutic strategies rely on culture-guided systemic
antibiotics, especially in older patients, in whom MRSA may be
Bacterial Infections the causative agent. Steroids may be used in selected cases in
Poststreptococcal Glomerulonephritis which crescents and severe interstitial inflammation are present.
Poststreptococcal glomerulonephritis is the best-studied and
classic immune complex–mediated glomerulonephritis. It is the
result of skin or throat infection with nephritogenic strains of IgA Nephropathy
group A streptococci. The latent period between upper respiratory
infection and nephritis is 7–10 days, and 2–4 weeks after skin KeY COnCePtS
infection. Antistreptococcal antibody titers are usually measured
to demonstrate the existence of a preceding streptococcal infection. Immunoglobulin A Nephritis (IgAN)
Antistreptolysin O titers and anti-DNase B titers are the most • Common cause of asymptomatic microscopic hematuria, recurrent
frequently elevated in upper respiratory and skin infections, macroscopic hematuria, and/or low-grade proteinuria
respectively. • Spectrum of disease, including idiopathic IgA nephritis and Henoch-
Poststreptococcal glomerulonephritis is characterized by a Schönlein purpura nephritis; IgA in skin and renal biopsy samples
nephritic syndrome consisting of smoky or rust-colored urine, • Mostly benign prognosis, especially in children
generalized edema, hypertension, and nephritic urine sediment. • Patients with progressive renal insufficiency and/or crescentic glo-
Proteinuria is typically mild. Patients have rising titers of anti- merulonephritis warrant trial of glucocorticoids and/or cytotoxic drug
therapy
streptolysin and depressed C3 levels early in nephritis but normal
926 Part Seven Organ-Specific Inflammatory Disease
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FIG 68.10 Immunoglobulin A Nephropathy (IgAN). (A) hematoxylin and eosin (H&E) stain and
(B) periodic acid–Schiff (PAS) stain: Glomeruli manifest modestly increase mesangial hypercellularity
and expanded mesangial matrix. C, Immunofluorescence showing predominantly IgA deposition
within the mesangium. D, Electron microscopy showing deposits mainly within the mesangium
but not along peripheral capillary loops.
IgA nephropathy (IgAN) is the most common primary glomeru-
32
lonephritis worldwide. IgAN can affect patients of all ages, Pathology
34
especially children and young adults, with a male preponderance. The characteristic findings on light microscopy are mesangial
32
There are geographical and ethnic differences in the prevalence cell proliferation and mesangial matrix expansion. Electron
of IgAN. The highest frequency is found among East Asians; microscopy typically reveals electron-dense deposits that are
IgAN is very uncommon in individuals of African ancestry. primarily limited to the mesangium, but a few deposits may also
This observation and examples of familial clustering of IgA be present in subendothelial and subepithelial locations. The
nephropathy favor an important element of genetic susceptibility. pathognomonic finding on immunofluorescence microscopy is
IgAN may be discovered during evaluation of asymptomatic globular deposits of IgA (often accompanied by C3 and IgG) in
34
microscopic hematuria. Alternatively, patients (especially children) the mesangium and, to a lesser degree, along the glomerular
can present with recurrent episodes of macroscopic hematuria capillary wall (Fig. 68.10).
that occur within 24–48 hours after an intercurrent infection,
usually an upper respiratory or gastrointestinal (GI) tract infection. Etiology and Pathogenesis
A transient elevation in serum creatinine has been associated with Aberrant glycosylation of O-linked glycans in the hinge region
macroscopic hematuria in about one-third of cases. This has been of IgA1 resulting in increased serum levels of galactose-deficient
34
attributed to tubular injury and obstruction caused by intraluminal IgA1 (Gd-IgA1) plays a pivotal role in pathogenesis of IgAN.
RBC casts. A small percentage of patients present with either The aberrantly glycosylated IgA1 is recognized by antiglycan
nephrotic syndrome or an acute RPGN picture characterized by antibodies and leads to circulating IgA immune complexes that
edema, hypertension, renal insufficiency, and hematuria. preferentially deposit in the mesangium, provoking local injury.
CHaPter 68 Immunological Renal Diseases 927
A genetic predisposition to IgAN has been linked with poly- TABLE 68.2 Prevalence of antineutrophil
morphisms involving innate and adaptive immunities and the Cytoplasmic antibodies (anCas) in
alternative complement pathway. A “second hit” may be needed renal vasculitis
in predisposed individuals. Infections may play a role because
episodes of macroscopic bleeding often coincide with mucosal anCaS teSt POSItIvItY (%)
infections, including upper respiratory tract (synpharyngitic) P-anCas or C-anCas or
or GI infections.
type of renal vasculitis anti-Mpo anti-Pr3
Natural History Polyarteritis nodosa 10–20 10–20
Patients with IgAN who have low-grade proteinuria (<1 g/day) Microscopic polyangiitis 50–80 10–20
80–90
10–20
Granulomatosis with
have a good renal prognosis and usually have a low risk of progres- polyangiitis (Wegener
sion. However, it is recognized that at least one-third of patients granulomatosis)
34
with IgAN eventually progress to ESKD. Twenty years after Necrotizing and crescentic GN 50–80 10–20
apparent disease onset, the probability of renal failure is 25%,
and the probability of some renal dysfunction is 50%. Hyperten- MPO, myeloperoxidase; PR3, proteinase 3.
sion occurs frequently as the disease progresses and forebodes
a poor prognosis. Other clinical features that have been associated granulomatosis), eosinophilic granulomatosis with polyangiitis
with a poor prognosis include older age at disease onset, persistent (EGPA, formerly Churg-Strauss syndrome), and renal limited
proteinuria (>1 g/day), and persistent azotemia. vasculitis. As shown in Table 68.2, the patterns of ANCAs differ,
depending on the type of vasculitis.
Treatment Renal involvement is common in AAV but varies in type and
The most effective treatment of progressive IgAN remains severity. It occurs more frequently in MPA (90%) and in GPA
34
undefined and controversial. Angiotensin antagonists are recom- (80%) and less frequently in EGPA (45%). Clinically RPGN is
mended to achieve blood pressure control, to reduce proteinuria, a common manifestation of these renal vasculitides characterized
and to slow the rate of deterioration of renal function. There by the presence of hematuria, proteinuria, active urinary sedi-
are conflicting data about the value of fish oil dietary supplements ments, and renal failure.
(eicosanoids) in preventing renal progression in patients with
IgAN. The practice of tonsillectomy in IgAN has not been Pathology
confirmed. A large trial (STOP-IgA nephropathy) showed that The glomerular abnormalities are similar among the subtypes
immunosuppression (glucocorticoid monotherapy or a regimen of ANCA-associated glomerulonephritides (Fig. 68.11). The
that included prednisolone, cyclophosphamide, and azathioprine) glomerular lesions are characteristically focal and segmental in
did not have a significant beneficial effect on preservation of distribution, with fibrinoid necrosis and crescent formation.
33
kidney function. However, a course of oral steroids may be Breaks in the GBM may be seen. There may be accompanying
considered in patients with high-grade proteinuria, and cytotoxic necrotizing arteritis. In contrast to immune complex–mediated
drugs are indicated in a small subset of patients with crescentic vasculitis, ANCA-associated vasculitis has little or no Ig deposition
rapidly progressive IgAN. The lack of effective therapy have in injured glomerular vessels, with minimal or negative staining
provided the impetus for several new phase II/III clinical trials by immunofluorescence, a so-called pauci-immune pattern.
testing novel therapies, such as B-cell activating factor (BAFF) Patients with large percentage of cellular crescents (>50%)
inhibition, proteasome inhibition, and B-cell inhibition. 34,35 typically present with severely reduced renal function but have
a good chance for recovery of renal function with treatment,
Renal Vasculitis Associated With Antineutrophil whereas those with a greater percentage of globally sclerotic
Cytoplasmic Antibodies glomeruli are less likely to recover renal function. 36
Treatment and Prognosis
KeY COnCePtS ANCA-associated renal vasculitis tends to be severe and fulminant,
Antineutrophil Cytoplasmic Antibodies (ANCAs)– making early detection critically important in management. Even
Associated Renal Vasculitis with early diagnosis, approximately one-third of patients will
progress to renal failure within 5 years. Relapsing courses are
• Renal vasculitis with glomerular involvement includes microscopic common in patients with microscopic polyangiitis, particularly
polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and necrotiz- GPA. This underscores the importance of prompt induction
ing crescentic glomerulonephritis (renal-limited vasculitis)
• Associated with ANCAs treatment followed by maintenance therapy. Glucocorticoids
• Rapidly progressive glomerulonephritis is common; early treatment are important in the early treatment of renal vasculitis.
includes pulse methylprednisolone, cyclophosphamide, rituximab, or Cyclophosphamide-based regimens are very effective in inducing
possibly plasma exchange remission in patients with AAVs. Most advocate daily oral
• Maintenance therapy: azathioprine, rituximab cyclophosphamide regimens, but intermittent pulse cyclophos-
phamide may be substituted to reduce the toxicity of extended
therapy. In patients with severe pulmonary hemorrhage or rapidly
ANCAs are associated with a distinct form of vasculitis that can progressive glomerulonephritis caused by renal vasculitis, pulse
affect many different types of vessels and any organ in the body. methylprednisolone, followed by prednisone and daily cyclo-
ANCA-associated vasculitis (AAV; Chapter 58) is categorized phosphamide, is clearly indicated. Adjunctive plasma exchange
into four main types: microscopic polyangiitis (MPA), granu- is commonly used in cases of aggressive pulmonary–renal
lomatosis with polyangiitis (GPA, formerly called Wegener syndrome. Rituximab has become a valuable alternative to
928 Part Seven Organ-Specific Inflammatory Disease
$ %
& '
FIG 68.11 Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Systemic Vasculitis.
A, Skin biopsy showing leukocytoclastic vasculitis of a small dermal artery (hematoxylin and eosin
[H&E] stain). B, Glomerulus illustrating a characteristic segmental proliferative lesion forming an
adhesion to the Bowman capsule in an early and mild case (H&E stain). C, Glomerulus with
classical fibrinoid necrosis and an associated cellular crescent of a more severe and rapidly progres-
sive case (H&E stain). D, Necrotizing vasculitis in a small renal artery in an extreme case of
ANCA-associated renal vasculitis; large numbers of eosinophils are present in the perivascular
inflammatory infiltrate (H&E stain).
cyclophosphamide for induction treatment based on the results Goodpasture disease is a rare but classic immune-mediated cause
of two pivotal prospective randomized controlled trials. 37,38 of severe pulmonary–renal syndrome. The cardinal pathogenic
Maintenance therapy is usually given for 12–18 months after factor is an autoantibody to a component of type IV collagen
achieving remission. Azathioprine has been the mainstay of (noncollagenous domain 1 of the α 3 chain subunit) within the
maintenance therapy in AAVs after remission induction, but GBM or the alveolar basal membrane. 40,41 These autoantibodies
rituximab is also likely to have a prominent role in maintenance lead to GBM rupture with development of crescentic glomeru-
therapy, as indicated by favorable results from preliminary trials. 39 lonephritis (Fig. 68.12) and account for the pathognomonic
finding of linear deposition of IgG along the glomerular capillaries
Anti-GBM Antibody-Mediated Nephritis: as assessed by immunofluorescence microscopy.
Goodpasture Disease The genesis of anti-GBM antibodies in sporadic cases is
unknown. It is postulated that an inciting event(s) (i.e., viral
KeY COnCePtS infection or exposure to environmental factor, such as hydro-
Goodpasture Disease carbons, tobacco) perturbs the normal conformation of collagen
in the basement membrane, exposing previously cryptic epitopes
• Circulating anti–glomerular basement membrane (GBM) antibody on the α 3 subunit, eliciting the pathogenic autoantibody response.
• Associated with pulmonary hemorrhage Iatrogenic cases have occurred when normal kidneys have been
• Rapidly progressive glomerulonephritis with cellular crescents and transplanted into patients with hereditary Alport nephropathy
linear deposits of immunoglobulin G (IgG)
• Treated with high-dose steroids, cyclophosphamide, plasma exchange (which is caused by mutations in the α 5 chain of type IV collagen).
The absence of expression of α 5 (and associated lack of α 3 and
CHaPter 68 Immunological Renal Diseases 929
Caucasians. Nephritis is a major cause of morbidity and mortality
and accounts for a large portion of all hospital admissions in
patients with SLE.
Pathogenesis
Several different mechanisms appear to be involved in the
pathogenesis of lupus nephritis, resulting in a wide spectrum of
renal lesions. Deposition of immune complexes from the circula-
tion into the kidney appears to be the initiating event in prolifera-
tive lupus nephritis; however, only a subset of immune complexes
appears to be nephritogenic. DNA and anti-DNA antibodies are
known to be concentrated in glomerular deposits in the suben-
dothelial location and are likely to play a central role in the
pathogenesis of proliferative lupus nephritis. Unfortunately, there
are fewer insights into the pathogenesis of lupus MN with its
characteristic epimembranous immune deposits. Although T
cells are almost certainly involved in autoantibody production,
FIG 68.12 Goodpasture Disease. Circumferential cellular it is unknown whether they have a direct role in the pathogenesis
crescent fills the Bowman capsule and compresses the glomerular of lupus nephritis.
tuft (Silver stain).
Clinical Features
Asymptomatic hematuria or proteinuria may be the presenting
α 4 ) means that these molecules within the renal allograft are features, but they often progress to nephritic and/or nephrotic
regarded as foreign antigens. Thus recipients mount an anti-GBM syndrome. Hypertension, azotemia, nephritic urine sediment
antibody response to the new donor antigens. (with hematuria and cellular casts), hypocomplementemia and
Clinically malaise, weight loss, fever, or arthralgia may be the high anti–double-stranded DNA (dsDNA) titers are more com-
initial features of anti-GBM disease. Some patients present with monly found in patients with proliferative lupus nephritis. RPGN
isolated renal involvement, but more typically, pulmonary is usually associated with the appearance of cellular crescents
hemorrhage with hemoptysis accompanies acute renal failure. and may be superimposed on severe proliferative or membranous
The devastating nature of the disease warrants aggressive treat- forms of lupus nephritis.
ment. Pulse methylprednisolone, cyclophosphamide, and plasma
exchange are indicated early in the course of Goodpasture Pathology
42
disease. The role of rituximab in this disease requires further The former classification of renal biopsy in lupus nephritis by
study. Reversibility of renal disease is unlikely if renal function the World Health Organization (WHO) was revised by an
is substantially impaired or oliguria ensues before treatment is international committee in 2004 (Figs. 68.13 to 68.15). A summary
started. Immunosuppressive treatment is normally continued of the histological features in each class of lupus nephritis can
until the patient has been in sustained clinical remission and be found in Table 68.3.
anti-GBM titers are minimal or absent for at least 3 months.
Treatment
Lupus Nephritis In 2012, the American College of Rheumatology (ACR), the
European League Against Rheumatism (EULAR), and the Euro-
KeY COnCePtS pean Renal Association–European Dialysis and Transplantation
Lupus Nephritis Association (ERA-EDTA) published their recommendations for
the management and treatment of patients with lupus nephri-
• Class I: normal glomeruli by light microscopy in patients with SLE. tis. 43,44 Immunosuppressive treatment of mesangial classes of
• Class II, mesangial: Immunosuppressive treatment is usually not lupus nephritis (classes I and II) is usually not indicated (ACR).
indicated unless patient has proteinuria >1 g/day despite renin–angio- However, the distinction between early mesangial lesions that
tensin–aldosterone (RAA) system blockade, especially if urine sediment
is nephritic are in transition to more ominous classes from those that reflect
• Class III, focal nephritis and class IV, diffuse nephritis: Mycophenolate mild and stable nephropathy is difficult. Consequently, treatment
mofetil (MMF) or intravenous cyclophosphamide (IVCY) plus gluco- with prednisone alone or in combination with azathioprine has
corticoids for induction followed by MMF or azathioprine plus low-dose been recommended for patients with proteinuria that exceeds
corticosteroids as maintenance therapy 1 g/day despite blockade of the renin–angiotensin–aldosterone
• Class V, Membranous nephropathy: Alternate-day prednisone with (RAA) system, especially if the patient also has a nephritic
MMF, or alternatively bimonthly pulse cyclophosphamide or low-dose urinary sediment (EULAR/ERA-EDTA). For patients with focal
daily cyclosporine
or diffuse proliferative glomerulonephritis (classes III and IV),
ACR and EULAR/ERA-EDTA recommended mycophenolate
Glomerular disease affects the majority of patients with SLE mofetil (MMF) or intravenous cyclophosphamide (IVCY) plus
(Chapter 51), but lupus nephritis has a wide spectrum of disease glucocorticoids. Low-dose IVCY (500 mg IV every 2 weeks in
expression and outcomes among different patient populations. six doses) offers a favorable balance of efficacy and relatively
Lupus nephritis occurs more often and is associated with less low toxicity for Caucasian patients with Western or Southern
favorable outcomes among Hispanic, Asian, Native American, European ancestry. Higher dose, monthly IVCY for 6 months, plus
and especially African American populations compared with 3 daily IV infusions of methylprednisolone initially, followed by
930 Part Seven Organ-Specific Inflammatory Disease
$ %
FIG 68.13 Classes of the Pathology of Lupus Nephritis (1). A, Class II, mesangial proliferative
lupus nephritis; mesangial areas are expanded by cells and matrix but the peripheral capillary
loops remain widely patent (periodic acid–Schiff [PAS] stain). B, Class III, focal lupus nephritis;
solid lesion at the lower right portion of this glomerulus demonstrates segmental fibrinoid necrosis.
Note the nuclear fragments (karyorrhexis) in the fibrinous exudate (hematoxylin and eosin [H&E]
stain.)
$ %
FIG 68.14 Classes of the Pathology of Lupus Nephritis (2). A, Class IV, diffuse lupus nephritis;
glomerulus with irregular but nearly global changes, including obliteration of many capillary loops
resulting from endocapillary hypercellularity, “wire loop” thickening and hyaline thrombi (periodic
acid–Schiff [PAS] stain). B, Class V, membranous lupus nephritis; glomerulus shows minimally
increased mesangial cellularity with thickened but widely patent capillary loops (PAS stain).
prednisone has also been recommended for patients with ominous EULAR/ERA-EDTA recommended at least 3 years of therapy in
clinical and histological prognostic indicators, including cellular patients showing improvement after initial therapy. In general,
crescents and fibrinoid necrosis. ACR and EULAR/ERA-EDTA we have offered a comparable recommendation that treatment
recommended either azathioprine (AZA) or MMF as maintenance should continue for at least 1 year after remission of renal disease
therapy for patients showing a favorable response after initial to prevent exacerbations.
immunosuppressive therapy. Although AZA and MMF appeared Neither IVCY nor MMF is universally effective in the manage-
to be equally effective maintenance therapies in a European study, ment of lupus nephritis, hence the search for more efficacious
patients randomized to maintenance therapy with MMF had treatment regimens, including rituximab, belimumab (binds to
more favorable outcomes than those randomized to AZA in a BAFF), immunomodulators (e.g., laquinimod), cytokine inhibi-
larger study conducted worldwide. The duration of maintenance tors, immunoablation without or with stem-cell reconstitution,
immunosuppressive therapy involves careful consideration of the and immunological costimulation inhibitors (e.g., CTLA-4-Ig),
risks of another renal flare-up versus the risks of drug toxicity. continues. 35,45 The importance of these ongoing efforts to
CHaPter 68 Immunological Renal Diseases 931
For patients with “pure” class V lupus MN and nephrotic-range
proteinuria, both the ACR and the EULAR/ERA-EDTA have
recommended oral prednisone and MMF. A prospective controlled
trial showed that both IVCY and CSA were more effective than
steroids alone in inducing remission of proteinuria in lupus MN
but that relapse of nephrotic syndrome occurred significantly
more often in the CSA group than in the IVCY treatment group.
Scleroderma (Systemic Sclerosis) Renal Disease
KeY COnCePtS
Nephropathies of Selected Connective
Tissue Diseases
• Scleroderma renal crisis: Predominantly renal vasculopathy; moderate
to severe (high renin) hypertension with progressive renal failure—
treated with angiotensin-converting enzyme inhibitors (ACEIs); additional
FIG 68.15 Ultrastructure of Proliferative Lupus Nephritis. antihypertensive agents may be needed
Electron micrography demonstrates the characteristic mesangial • Sjögren syndrome: Distal renal tubular acidosis, nephrogenic diabetes
deposits (dark materials interspersed within the centrally located insipidus, interstitial nephritis, hypokalemia, and/or renal calculi; glo-
amorphous, gray mesangial matrix) and subendothelial deposits merulonephritis rare
(dark materials extending along the peripheral capillary loops).
The most common and potentially devastating renal manifes-
tation of systemic sclerosis (Chapter 55) is scleroderma renal
TABLE 68.3 International Society of crisis (SRC). Most cases of SRC occur within 4 years of the
47
nephrology/renal Pathology Society 2004 onset of systemic sclerosis in patients with diffuse cutaneous
Classification of Lupus nephritis scleroderma affecting the proximal extremities and the trunk.
Several features, including rapid progression of skin thicken-
Class Histologic Features/Comments ing, palpable tendon friction rubs, anti-RNA polymerase III
I. Minimal Normal light microscopy (LM); mesangial deposits antibody, recent-onset cardiac events (e.g., pericardial effusion
mesangial by immunofluorescence (IF) and electron or heart failure), new-onset anemia (especially if associated
microscopy (EM) with microangiopathic hemolysis and thrombocytopenia), and
II. Mesangial Pure mesangial hypercellularity and matrix
proliferative expansion recent treatment with high-dose corticosteroids, help identify
IF and EM: mesangial immune deposits patients at increased risk for developing SRC. A classic clinical
III. Focal Glomerular capillary obliteration in <50% of presentation may obviate the need for renal biopsy. However, renal
nephrons as a result of proliferation or sclerosis biopsy may be necessary in atypical cases. For example, about
LM: Increased numbers of mesangial, endothelial, 20% of SRC cases occur before the diagnosis of scleroderma has
and/or hematogenous cells. Active inflammatory been established. Furthermore, patients with scleroderma have
lesions (karyorrhexis, fibrinoid necrosis, adhesion rarely developed other renal diseases, such as ANCA-associated
to the Bowman capsule, cellular crescents,
interstitial inflammatory infiltrates). Wire loop vasculitis, which are important to recognize because they
lesions. Hyaline thrombi require treatments different from those usually recommended
IF and EM: Mesangial and peripheral capillary loop for SRC.
(subendothelial) immune complex deposits Scleroderma renal crisis is characterized by abrupt onset of
IV. Diffuse Qualitatively similar histologic lesions as in class renin-mediated moderate to severe hypertension, rapid deteriora-
III. Glomerular capillary obliteration involving tion of renal function, and proteinuria (usually nonnephrotic).
>50% of nephrons. Subsets defined as primarily
global (class IV-G) or primarily segmental (class Associated findings may include microangiopathic hemolysis,
IV-S) involvement hypertensive encephalopathy (including seizures), and hyper-
V. Membranous LM: Regular thickening of the peripheral capillary tensive retinopathy, acute left ventricular failure, and pulmonary
loops of the glomerulus. Mesangial expansion edema. Normotensive renal crisis occurs infrequently and may
EM: Subepithelial, intramembranous, mesangial be recognized by the presence of microangiopathic hemolysis
(but no or very rare subendothelial) immune and/or unexplained azotemia. The primary pathogenic process
complex deposits
VI. Advanced >90% global sclerosis without residual active appears to be a renal vasculopathy involving predominantly the
lesions interlobular arteries and arterioles. Marked intimal thickening
with an attendant “mucoid” appearance, and fibrinoid necrosis
in the absence of vasculitis, are common and characteristic of
the disease (Fig. 68.16). Immune deposits are rarely observed
investigate novel approaches to treatment is underscored by by fluorescence or electron microscopy studies.
observations that although the risk of renal failure caused by Although a variety of treatments have been proposed for
lupus nephritis decreased from the 1970s to the mid-1990s patients with scleroderma, none has been proven to be con-
(coincident with the increased use of cyclophosphamide), that sistently efficacious. The most significant therapeutic advance
risk has shown a reverse trend and increased slightly in the last in the treatment of SRC is the use of angiotensin-converting
two decades. 46 enzyme (ACE) inhibitors (ACEIs), which have dramatically
932 Part Seven Organ-Specific Inflammatory Disease
On tHe HOrIZOn
• The advent of new genetic and molecular techniques and new disease
models has led to exciting progress in our understanding of the biology
of the glomerulus, the pathogenesis of many glomerular diseases,
and the influence of genetic variants on disease predisposition and
progression.
• It is anticipated that these insights should lead to better noninvasive
diagnostic techniques, biomarkers, and predictors of prognosis and
relapse and facilitate a more personalized approach to therapy rather
than a one-size-fits-all approach.
• Novel targeted therapies are on the horizon that will interrupt or
modulate the underlying pathophysiology of the individual diseases
and also halt the downstream pathways of injury and fibrosis common
to all of the glomerular diseases.
FIG 68.16 Scleroderma Renal Crisis. Renal arteriole demon-
strates extensive fibrin deposition (dark material) within multiple Please check your eBook at https://expertconsult.inkling.com/
layers of its wall. The lumen is further compromised by severe for self-assessment questions. See inside cover for registration
swelling and intimal hyperplasia (Masson trichrome stain). details.
REFERENCES
1. Couser WG, Johnson RJ. The etiology of glomerulonephritis: roles of
infection and autoimmunity. Kidney Int 2014;86:905–14.
increased the 1-year survival of patients with SCR. Prompt 2. Mastroianni-Kirsztajn G, Hornig N, Schlumberger W. Autoantibodies in
treatment with ACEIs is recommended for hypertensive and renal diseases - clinical significance and recent developments in
normotensive SRC because these agents may reverse the process serological detection. Front Immunol 2015;6:221.
by interfering with angiotensin II–mediated vasoconstriction 3. Floege J, Amann K. Primary glomerulonephritides. Lancet
2016;387:2036–48.
and by inhibiting the degradation of the potent vasodilator 4. Waldman M, Crew RJ, Valeri A, et al. Adult minimal-change disease:
bradykinin by ACE. Despite this impressive impact of ACEIs clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol
on clinical outcomes, approximately one-third to one-half of 2007;2:445–53.
patients still progress to early death or renal failure. This has 5. Maas RJ, Deegens JK, Wetzels JF. Permeability factors in idiopathic
prompted continued investigation of additional treatment strate- nephrotic syndrome: historical perspectives and lessons for the future.
gies, including blockade of the RAA system at multiple sites Nephrol Dial Transplant 2014;29:2207–16.
(using, for example, a direct renin inhibitor) as well as addition 6. Fornoni A, Sageshima J, Wei C, et al. Rituximab targets podocytes in
of potent vasodilators (e.g., prostacyclin or an endothelin receptor recurrent focal segmental glomerulosclerosis. Sci Transl Med
antagonist). 2011;3:85ra46.
7. Yu CC, Fornoni A, Weins A, et al. Abatacept in B7-1-positive proteinuric
Renal Disease of Sjögren Syndrome kidney disease. New Engl J Med 2013;369:2416–23.
8. D’Agati VD, Alster JM, Jennette JC, et al. Association of histologic
A variety of renal manifestations occur in approximately one-third variants in FSGS clinical trial with presenting features and outcomes. Clin
of patients with primary Sjögren syndrome (Chapter 54), includ- J Am Soc Nephrol 2013;8:399–406.
ing tubular dysfunction (proximal or, more often, distal tubular 9. Fernandez-Fresnedo G, Segarra A, Gonzalez E, et al. Rituximab treatment
acidosis, Fanconi syndrome, hypokalemia that may be profound of adult patients with steroid-resistant focal segmental glomerulosclerosis.
and associated with paralysis, Bartter syndrome, Gitelman Clin J Am Soc Nephrol 2009;4:1317–23.
syndrome, nephrogenic diabetes insipidus), as well as renal calculi, 10. Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset,
nephrocalcinosis, interstitial nephritis, pseudolymphoma, nec- complicated, frequently relapsing nephrotic syndrome or
48
rotizing vasculitis, and glomerulopathy. Studies of renal steroid-dependent nephrotic syndrome: a multicentre, double-blind,
randomised, placebo-controlled trial. Lancet 2014;384:1273–81.
pathology among patients with primary Sjögren syndrome have 11. Malaga-Dieguez L, Bouhassira D, Gipson D, et al. Novel therapies for
shown that acute and/or chronic tubulointerstitial nephritis is FSGS: preclinical and clinical studies. Adv Chronic Kidney Dis
the predominant lesion. A diverse range of glomerular diseases, 2015;22:e1–6.
including MN and proliferative glomerulonephritis (focal or 12. Coppo R. Different targets for treating focal segmental glomerular
diffuse, and membranoproliferative), have been reported in sclerosis. Contrib Nephrol 2013;181:84–90.
primary Sjögren syndrome. In such cases, the possibility of overlap 13. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2
with SLE should be considered. Immunosuppressive therapy for receptor as target antigen in idiopathic membranous nephropathy. N
renal manifestations of primary Sjögren syndrome should be Engl J Med 2009;361:11–21.
individualized on the basis of activity and severity of the glo- 14. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, et al. Thrombospondin
merular and/or tubulointerstitial nephritis. Patients with serious type-1 domain-containing 7A in idiopathic membranous nephropathy.
New Engl J Med 2014;371:2277–87.
complications of tubular dysfunction may warrant immunosup- 15. Hoxha E, Thiele I, Zahner G, et al. Phospholipase A2 Receptor
pressive therapies based on preliminary evidence that autoantibod- Autoantibodies and Clinical Outcome in Patients with Primary
ies (against, for example, carbonic-anhydrase-II) as well as Membranous Nephropathy. J Am Soc Nephrol 2014;25:1357–66.
cell-mediated injury likely contribute to at least some of those 16. Waldman M, Austin HA 3rd. Treatment of idiopathic membranous
disorders. nephropathy. J Am Soc Nephrol 2012;23:1617–30.
CHaPter 68 Immunological Renal Diseases 933
17. Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of 33. Rauen T, Eitner F, Fitzner C, et al. Intensive Supportive Care plus
idiopathic membranous nephropathy. Kidney Int 2008;73:117–25. Immunosuppression in IgA Nephropathy. N Engl J Med
18. Fervenza FC, Abraham RS, Erickson SB, et al. Rituximab therapy in 2015;373:2225–36.
idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc 34. Wyatt RJ, Julian BA. IgA Nephropathy. N Engl J Med 2013;368:2402–14.
Nephrol 2010;5:2188–98. 35. Karras A, Jayne D. New biologics for glomerular disease on the horizon.
19. Remuzzi G, Chiurchiu C, Abbate M, et al. Rituximab for idiopathic Nephron 2014;128:283–91.
membranous nephropathy. Lancet 2002;360:923–4. 36. Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of
20. Pickering MC, D’Agati VD, Nester CM, et al. C3 glomerulopathy: ANCA-associated glomerulonephritis. J Am Soc Nephrol
consensus report. Kidney Int 2013;84:1079–89. 2010;21:1628–36.
21. Fakhouri F, Fremeaux-Bacchi V, Noel LH, et al. C3 glomerulopathy: a 37. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide
new classification. Nature Rev Nephrol 2010;6:494–9. for ANCA-associated vasculitis. N Engl J Med 2010;363:221–32.
22. De Vriese AS, Sethi S, Van Praet J, et al. Kidney Disease Caused by 38. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus
Dysregulation of the Complement Alternative Pathway: An Etiologic cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med
Approach. J Am Soc Nephrol 2015;26:2917–29. 2010;363:211–20.
23. Bertino G, Ardiri A, Proiti M, et al. Chronic hepatitis C: This and the new 39. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for
era of treatment. World J Hepatol 2016;8:92–106. maintenance in ANCA-associated vasculitis. N Engl J Med
24. Bruchfeld A, Lindahl K, Reichard O, et al. Pegylated interferon and 2014;371:1771–80.
ribavirin in haemodialysis patients. Nephrol Dial Transplant 40. Pedchenko V, Bondar O, Fogo AB, et al. Molecular architecture of the
2006;21:1444–5. Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med
25. Feng B, Eknoyan G, Guo ZS, et al. Effect of interferon-α-based antiviral 2010;363:343–54.
therapy on hepatitis C virus-associated glomerulonephritis: a 41. Greco A, Rizzo MI, De Virgilio A, et al. Goodpasture’s syndrome: a
meta-analysis. Nephrol Dial Transplant 2012;27:640–6. clinical update. Autoimmun Rev 2015;14:246–53.
26. Sise ME, Bloom AK, Wisocky J, et al. Treatment of hepatitis C 42. Pusey CD. Anti-glomerular basement membrane disease. Kidney Int
virus-associated mixed cryoglobulinemia with direct-acting antiviral 2003;64:1535–50.
agents. Hepatology 2016;63:408–17. 43. Hahn BH, McMahon MA, Wilkinson A, et al. American College of
27. Sneller MC, Hu Z, Langford CA. A randomized controlled trial of Rheumatology guidelines for screening, treatment, and management of
rituximab following failure of antiviral therapy for hepatitis C lupus nephritis. Arthritis care & research 2012;64:797–808.
virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 44. Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League
2012;64:835–42. Against Rheumatism and European Renal Association-European Dialysis
28. Saadoun D, Resche-Rigon M, Sene D, et al. Rituximab combined with and Transplant Association (EULAR/ERA-EDTA) recommendations for
Peg-interferon-ribavirin in refractory hepatitis C virus-associated the management of adult and paediatric lupus nephritis. Ann Rheum Dis
cryoglobulinaemia vasculitis. Ann Rheum Dis 2008;67:1431–6. 2012;71:1771–82.
29. Lan X, Rao TK, Chander PN, et al. Apolipoprotein L1 (APOL1) Variants 45. Mok CC. Towards new avenues in the management of lupus
(Vs) a possible link between Heroin-associated Nephropathy (HAN) and glomerulonephritis. Nature Rev Rheumatol 2016;12:221–34.
HIV-associated Nephropathy (HIVAN). Front Microbiol 2015;6:571. 46. Tektonidou MG, Dasgupta A, Ward MM. Risk of End-stage Renal Disease
30. Booth JW, Hamzah L, Jose S, et al. Clinical characteristics and outcomes in Patients with Lupus Nephritis, 1970 to 2015 A systematic review and
of HIV-associated immune complex kidney disease. Nephrol Dial Bayesian meta-analysis. Arthritis Rheumatol 2016;68:1432–41.
Transplant 2016;31:2099–107. 47. Mouthon L, Bussone G, Berezne A, et al. Scleroderma renal crisis. J
31. Nobakht E, Cohen SD, Rosenberg AZ, et al. HIV-associated immune Rheumatol 2014;41:1040–8.
complex kidney disease. Nature Rev Nephrol 2016;12:291–300. 48. Francois H, Mariette X. Renal involvement in primary Sjogren syndrome.
32. Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA Nature Rev Nephrol 2016;12:82–93.
nephropathy: rationale, clinicopathological correlations, and classification.
Kidney Int 2009;76:534–45.
CHaPter 68 Immunological Renal Diseases 933.e1
MUL t IPL e -CHOIC e QU e S t IO n S
1. A 45-year-old woman presented to the emergency department was afebrile, and his blood pressure was 140/80 mm Hg. The
(ED) with swelling in both ankles, 15-lb weight gain over the catheter site was clean, and the remainder of the examination
past 3 months and shortness of breath. During a physical was unremarkable. There was trace edema. Laboratory findings
examination 1 year prior, 1+ protein was noted on dipstick were notable for mild hypoalbuminemia (serum albumin of
urinalysis, but no further workup was done. There was no 3.1 g/dL), serum creatinine of 2.1 mg/dL, hypocomplement-
family history of renal disease. The patient has blood pressure emia (C3, 4 mg/dL, C4, 5 mg/dL, and CH50, 10 U/mL).
of 120/80 mm Hg, elevated respiratory rate of 25, and oxygen Urinalysis was notable for proteinuria 2+, and urine microscopy
saturation of 90%. Physical examination was notable for pitting revealed 15 acanthocytes per high-power field. The spot urine
edema in her legs up to the mid-thighs. Lungs were clear. protein/creatinine ratio was 1.8 g/g. Human immunodeficiency
Laboratory testing revealed a hemoglobin level of 14 g/dL, virus (HIV), antinuclear antibody (ANA), and hepatitis B
hematocrit of 42%, serum creatinine level of 1.0 mg/dL, blood and C screen results were negative. Renal biopsy was performed
urea nitrogen (BUN) of 28 mg/dL, albumin level of 1.6 g/ after admission. Light microscopy (LM) revealed diffuse
dL, serum total cholesterol level of 350 mg/dL (normal, mesangial and endocapillary hypercellularity, lobulation in
<200 mg/dL), and serum triglyceride level of 800 mg/dL the glomeruli, and double contours in the glomerular capillary.
(normal, <150 mg/dL). Serum complement levels were within Two of 18 glomeruli had segmental crescents. Immunofluo-
normal limits. Urinalysis demonstrated 4+ protein on dipstick. rescence microscopy revealed staining for IgG (3+) and C3
Urine microscopy revealed 0–2 nondysmorphic red blood (3+) along the capillary and mesangial regions in a granular
cells per high-power field, oval fat bodies, and fatty casts. A pattern. Electron microscopy (EM) revealed subendothelial
spot protein/creatinine ratio was 8 g/g. The chest radiography and mesangial electron-dense deposits. What further workup
result was negative. Computed tomography (CT) angiography is indicated?
revealed multiple pulmonary emboli, and therapeutic anti- A. ANCAs testing
coagulation was immediately initiated. Renal biopsy was B. Anti–glomerular basement membrane (GBM) antibody
deferred because of the need for urgent anticoagulation. What C. Blood culture
would have been the most likely biopsy finding if biopsy had D. Evaluation for genetic mutations of complement regulatory
been done? proteins, including complement factor H (CFH), CFI, and
A. Acute post infectious glomerulonephritis Membrane cofactor protein (MCP).
B. Alport syndrome 3. A 60-year-old male with new diagnosis of Hodgkin lymphoma
C. Antineutrophil cytoplasmic antibodies (ANCAs)–associated was noted to have 3+ edema on examination by his oncologist.
crescentic glomerulonephritis Serum creatinine was 1.1 mg/dL. Serum albumin was 2.5 g/
D. Membranous nephropathy (MN)
dL. Urinary protein excretion revealed 6 g/24 hr. Urine
2. A 20-year-old male with history of short bowel syndrome microscopy showed fatty casts but no cellular elements. Kidney
was admitted to the hospital with elevated creatinine, mac- biopsy result was consistent with minimal change disease
roscopic hematuria and proteinuria, and renal insufficiency. (MCD). What is the appropriate treatment?
He had been on long-term peripheral nutrition via a central A. High-dose prednisone
venous catheter for 4 years. He was admitted 6 months ago B. Cyclosporine with prednisone
with a line infection and was given antibiotics for 7 days, but C. Mycophenolate mofetil
the line was not removed. He was noted to have trace pro- D. Chemotherapy
teinuria and hematuria 6 months ago. Upon admission, he
69
Inflammation and Atherothrombosis
Giovanna Liuzzo, Daniela Pedicino, Davide Flego, Filippo Crea
2
The spectrum of the clinical syndromes caused by coronary (Table 69.1). The atherogenic process develops over the course
atherosclerosis ranges from asymptomatic disease and stable of decades, beginning in the early teenage years. It is the same
angina (SA) to acute coronary syndromes (ACSs). The latter worldwide, regardless of gender and race, and proceeds at a
include unstable angina (UA) and acute myocardial infarction faster speed in patients with risk factors such as hypertension,
(MI), which is further classified according to electrocardiographic tobacco smoking, diabetes mellitus, obesity, and genetic predis-
changes as non-ST elevation myocardial infarction (NSTEMI) position. In the early phase, this process is triggered by suben-
and ST elevation myocardial infarction (STEMI), and sudden dothelial retention of cholesterol-containing plasma lipoproteins
cardiac death. and by flow-mediated inflammatory changes in endothelial cells
Although the early outcome of ACS has considerably improved (Table 69.2). At this stage of the disease, endothelial cells show
in the past decade, cardiovascular diseases still represent the an altered response to vasodilator and vasoconstrictor stimuli,
main cause of morbidity and mortality worldwide, mainly because due in part to nitric oxide reduction as well as to increased
chronic-smoldering ACS eventually leads to heart failure and expression of endothelin. Moreover, the cells express increased
sudden cardiac death. The gravity of the syndrome calls for a levels of adhesion molecules such as intercellular adhesion
reappraisal of the mechanisms responsible for coronary instability molecule (ICAM) and vascular cell adhesion molecule (VCAM)
and for innovative preventive and therapeutic strategies. and produce higher levels of chemotactic molecules such as
The life-threatening complications of coronary artery disease interleukin (IL)-8 and monocyte chemotactic protein (MCP),
arise as nonlinear events in an otherwise slowly progressive with the consequent increase in leukocytes’ recruitment. These
process. This nonlinearity has been attributed to a combination mechanisms act together to induce endothelial dysfunction
of factors, of which plaque rupture or erosion and superimposed and a chronic self-maintaining inflammatory state. Plaque forma-
thrombosis are considered to be the most important. Although tion is preceded by a fatty streak, an accumulation of lipid,
the pathways leading to plaque rupture or erosion are incompletely macrophages/foam cells, and T cells beneath the endothelium.
understood, our understanding of the importance of inflammation Fatty streaks may disappear or progress to atherosclerotic plaques,
in the process has considerably increased. Atherosclerosis is a asymmetrical focal thickenings of the intima with a core region
chronic inflammatory disease by itself, but an outburst of the of foam cells and extracellular lipids surrounded by a cap of
inflammatory process within the atherosclerotic plaque of coro- smooth-muscle cells and collagen. Atherosclerotic lesions contain
nary arteries can lead to plaque rupture with thrombosis, resulting monocyte-derived macrophages and T cells interspersed with
in myocardial ischemia and necrosis. The latter is an additional lipids and debris from dead cells; the lesions are embedded in
source for local and systemic inflammation. Furthermore, patients an extracellular matrix composed of collagen fibers and other
with ACS frequently undergo percutaneous coronary intervention constituents produced primarily by vascular smooth muscle cells.
(PCI), which may cause iatrogenic myocardial injury, a further T cells, macrophages, and mast cells infiltrate the lesion; they
source of inflammation. Moreover, plaque instability promotes are particularly abundant in the shoulder region of the atheroma,
hyperreactivity to the inflammatory stimulus of myocardial producing proinflammatory cytokines, costimulatory factors for
necrosis, which in turn accelerates plaque instability: Inflammation immune activation, eicosanoids, and reactive oxygen and nitrogen
begets inflammation (Fig. 69.1). Thus it is not surprising that a species. On the other hand, many immune cells beneath the
plethora of previous studies have consistently shown a marked plaque show antiinflammatory features: Macrophages internalize
elevation of circulating levels of high-sensitivity C-reactive protein cholesterol through their scavenger receptors and produce
(hs-CRP) or of other soluble markers of inflammation at the antiinflammatory cytokines, and T cells of the regulatory phe-
time of hospital admission. Interestingly, the intensity of this notype produce antiinflammatory and immunosuppressive
inflammatory surge predicts short- and long-term outcome. cytokines. The perturbation of this delicate balance between
Overall, these observations suggest that specific antiinflammatory pro- and antiinflammatory signals is involved both in the
treatment might improve the outcome of ACS. 1 nonresolving, chronic inflammation linked to disease progression
and in the eventual breakdown of endothelial continuity, with
ATHEROSCLEROSIS: A CHRONIC thrombus formation and plaque instability (Fig. 69.1). Fibrous
INFLAMMATORY DISEASE plaques appear in a later stage of the disease, with the chronic
accumulation of collagen and calcification. Erosion of the surfaces
Atherosclerosis is a chronic nonresolving inflammatory of some plaques and rupture of a plaque’s calcific nodule into
3
process that typically occurs at sites of blood flow disturbance the artery lumen may trigger thrombosis. Overall, mechanisms
935
936 Part seven Organ-Specific Inflammatory Disease
Early phases Late phases
Clinically silent Clinically silent or overt
Initial lesion Fatty streak Atheroma Fibroatheroma Complicated lesion
Macrophages Intracellular lipid Intra-and extra- Lipid core Endothelial damage
Foam cells accumulation cellular lipid Fibrosis Hematoma
NO reduction Leukocytes recruitment accumulation Calcification Thrombosis
ICAM/VCAM/
endothelin expression
FIG 69.1 Schematic Representation of the Natural History of Atherosclerotic Disease. This
figure shows the development of the atherogenic process. In the early phase, this process is
triggered by subendothelial retention of cholesterol-containing plasma lipoproteins and by flow-
mediated inflammatory changes in endothelial cells. Endothelial cells show an altered response
to vasodilator and vasoconstrictor stimuli, with nitric oxide (NO) reduction and increased expression
of endothelin. Moreover, they express increased levels of adhesion molecules such as intercellular
adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) and produce higher levels
of chemotactic molecules such as interleukin (IL)-8 and monocyte chemotactic protein (MCP),
with a consequent increase in leukocyte recruitment. The fatty streak is an accumulation of lipid,
macrophages/foam cells, and T cells beneath the endothelium. Fatty streaks may disappear or
progress to atherosclerotic plaques, asymmetrical focal thickenings of the intima with a core
region of foam cells and extracellular lipids surrounded by a cap of smooth-muscle cells and
collagen. Fibrous plaques appear at a later stage of the disease and are characterized by the
deposition of collagen and calcification.
TABLE 69.1 Key steps in atherogenesis TABLE 69.2 Factors Promoting endothelial
activation/Dysfunction in atherosclerosis
1. Endothelial activation with increased infiltration of atherogenic
lipoproteins at sites of low or oscillating shear stress (branch Reduced vasodilator and increased vasoconstrictor responsiveness
points and flow dividers). Enhanced oxidant stress with inactivation of nitric oxide
2. Subendothelial retention and modification of atherogenic Increased expression of endothelin
lipoproteins (low-density lipoprotein/very-low-density lipoprotein). Enhanced leukocyte (inflammatory cell) adhesion and recruitment
3. Endothelial activation with increased mononuclear leukocyte Increased adhesion molecule expression (ICAM, VCAM)
(inflammatory cell) adhesion, chemotaxis, and subendothelial Increased chemotactic molecule expression (MCP-1, IL-8)
recruitment. Increased prothrombotic and reduced fibrinolytic activity
4. Subendothelial inflammatory cell activation with lipid ingestion Increased growth-promoting phenotype
through monocyte scavenger receptor expression resulting in Dyslipidemia and atherogenic lipoprotein modification
foam cell formation. Elevated LDL, VLDL, LP(a)
5. Intimal migration and proliferation of medial/adventitial smooth- LDL modification (oxidation, glycation)
muscle cells/myofibroblasts in response to growth factors Reduced HDL
released by activated monocytes with matrix production and Increased angiotensin II and hypertension
formation of the fibrous cap and fibrous plaque. Estrogen deficiency
6. Abluminal plaque growth with positive (outward) arterial Smoking
adventitial remodeling preserving lumen size in early stages; Hyperhomocysteinemia
later, plaque growth or negative remodeling results in luminal Advancing age
narrowing. Infection?
7. Neoangiogenesis due to angiogenic stimuli produced by
inflammatory cells (macrophages) and other arterial wall cells HDL, high-density lipoprotein; ICAM, intercellular adhesion molecules; IL-8,
(vascular endothelial growth factor, interleukin-8). interleukin-8; LDL, low-density lipoprotein; LP, lipoprotein; MCP-1, monocyte
8. Death of foam cells by necrosis/apoptosis leading to necrotic chemotactic protein-1; VCAM, vascular cell adhesion molecules; VLDL, very-low-
lipid core formation. density lipoprotein.
9. Plaque disruption (rupture of fibrous cap or endothelial erosion)
due to inflammatory cell–mediated matrix degradation and death
of matrix-synthesizing smooth-muscle cells.
10. Exposure of thrombogenic substrate (lipid core–containing tissue
factor derived from inflammatory cells) following plaque
disruption with arterial thrombosis.
CHaPter 69 Inflammation and Atherothrombosis 937
responsible for coronary instability are multiple and insufficiently the cause of coronary instability in all patients. However, about
understood. 40% of ACS patients have low or very low levels of high-sensitivity
C-reactive protein (hs-CRP), a very sensitive marker of inflam-
ROLE OF INFLAMMATION IN THE PATHOGENESIS mation. Coronary angiography fails to demonstrate obstructive
4
OF ACUTE CORONARY SYNDROMES atherosclerosis in up to one-third of patients with symptoms
suggestive of an ACS along with raised troponin levels and/or
Experimental models of atherogenesis have provided a growing ischemic-like ST segment changes, suggesting that functional
body of information about molecular mechanisms of plaque alterations of epicardial arteries and/or of coronary microcircula-
growth; however, transition from coronary stability to instability tion may also play an important pathogenetic role. 5
is less well understood due to lack of animal models reflective We have recently proposed a pathogenetic classification of
1
of human disease. The abrupt clinical presentation of ACS gives ACS: (i) patients with plaque fissure and systemic inflammation;
a strong signal of discontinuity in the natural history of athero- (ii) patients with plaque fissure without systemic inflammation;
thrombosis. When primary prevention of atherosclerosis fails, (iii) patients with plaque erosion; and (iv) patients with smooth
the progression of coronary atherosclerosis can remain clinically plaques and functional alterations in the coronary circulation
silent for years, decades, or even for life, as indicated by the high (Fig. 69.2). For the first group, multiple studies have highlighted
prevalence of coronary atherosclerosis in subjects dying of the prominent role of inflammation in generating plaque instabil-
noncardiac causes. In contrast, some patients at a certain point ity, with three main features characterizing these ACS patients:
in their lives exhibit acute coronary instability, followed by a (i) the widespread involvement of epicardial arteries, coronary
period of stability that can be short or last for years or decades. microcirculation, and myocardium; (ii) the activation of innate
These simple clinical observations suggest that the mechanisms immunity; and (iii) the activation of adaptive immunity, with
responsible for plaque growth and for plaque instability are a consequent dysbalance between antiinflammatory and proin-
different and that the causes and mechanisms of plaque instability flammatory immune responses.
are multiple. Accordingly, the paradigm that implies a single In patients in whom plaque rupture and coronary instability
type of culprit coronary plaque as a cause for instability does occur in the absence of systemic evidence of inflammation, the
1
not adequately fit the findings of postmortem studies. The precise causes of instability are still poorly understood. However,
concept that inflammatory cell activation plays a key role in the mechanisms such as extreme emotional disturbance, intense
pathogenesis of ACS is now commonly accepted, and it is believed physical exertion, and local mechanical stress at the level of the
that activation of inflammatory cells in the culprit stenosis is artery wall are likely to play a key pathogenetic role.
ACUTE CORONARY SYNDROMES
A B
• SMCs hyperreactivity • Local thrombogenic stimuli
• Proximal and/or distal spasm • Monocytes/PMN
recruitment
White/red
thrombus
Smooth plaque Plaque erosion
C D
NO EVIDENCE OF EVIDENCE OF
SYSTEMIC SYSTEMIC
INFLAMMATION INFLAMMATION
• Local or systemic stressors Plaque fissure • Innate immunity activation
• Adaptive immunity activation
FIG 69.2 Pathogenetic Classification of Acute Coronary Syndromes. In patients with a similar
clinical presentation, mechanisms responsible for coronary instability can be significantly different.
The figure shows optical coherence tomography (OCT) images of different plaques and the
proposed pathogenetic classification of acute coronary syndromes (ACS). This classification is
based on the mechanisms responsible for coronary instability in homogeneous groups of patients:
(D) patients with plaque fissure and systemic inflammation; (C) patients with plaque fissure
without systemic inflammation; (B) patients with plaque erosion; (A) patients with functional
defects in coronary circulation. PMN, Ppolymorphonuclear neutrophil; SMCs, smooth muscle
cells (SMCs).
938 Part seven Organ-Specific Inflammatory Disease
The mechanisms of plaque erosion are still largely unknown, perfused by the culprit artery. This event appears unrelated to
although increasing evidence suggests that local neutrophil coronary atherosclerosis or recurrent ischemia, as it is not
activation possibly plays a role. observed in patients with chronic SA and multivessel coronary
11
Among the majority of patients who present with ACS in the disease or in patients with vasospastic angina. Widespread acute
absence of obstructive atherosclerosis, functional alterations of coronary inflammation is, therefore, the likely cause of multiple
epicardial coronary arteries or of coronary microcirculation are complex stenoses, multiple thrombi, and multiple fissured plaques
the likely cause of instability. involving different coronary artery branches observed in clinical
6
studies in ACS, based on angiography and intravascular imaging.
The number of disrupted coronary plaques correlates with
PLAQUE FISSURE WITH SYSTEMIC systemic hs-CRP levels. The notion of widespread coronary
INFLAMMATION inflammation is confirmed by postmortem studies. 1
Plaque fissure is caused by the combined action of metallopro- Activation of Innate Immunity
teinases, which digest the intercellular matrix and reduce collagen The notion that innate immunity plays an important role in
synthesis. This results in the exposure of the highly thrombogenic ACS is supported by the demonstration of activated monocytes,
content of the underlying lipid plaque that triggers occlusive or polymorphonuclear neutrophils (PMNs), eosinophils, and mast
subocclusive thrombus formation. cells not only at the site of plaque rupture but also in the whole
1
coronary circulation of patients with ACS (Fig. 69.3). High
Plaque Fissure: Pathological and Clinical Findings telomerase activity in PMNs has been reported coming from
The role played by plaque fissure was initially established in the culprit coronary plaque of patients with ACS, but not from
postmortem studies and then confirmed in vivo by using plaque of patients with SA or in PMNs from the peripheral
angioscopy, intravascular ultrasound, and, more recently, optical blood. Telomerase activity is normally absent in differentiated
coherence tomography (OCT), a light-based imaging technique cells such as PMNs. The only predictor of telomerase reactivation
with high spatial resolution. OCT allows the detection of intra- in coronary plaques of ACS patients was a short time interval
coronary thrombi and the precise measurement of fibrous cap from symptom onset to PMN sampling. Neutrophil apoptosis
thickness and plaque components such as lipid core, calcium has been identified as one of the key mechanisms to switch off
6
nodules, and microvessels. OCT has been used in clinical studies inflammation. Accordingly, delayed apoptosis of peripheral PMNs
to obtain more detailed information about the vulnerable plaque in ACS patients has been demonstrated. 12
and to find specific features to differentiate between erosion-prone Macrophages account for the majority of leukocytes in
and rupture-prone plaques. In particular, the high resolution of plaques. Plaque-resident macrophages differentiate from
OCT has recently clarified that in vivo plaque rupture is associated monocytes recruited from circulating blood. However, monocytes
with ACS in about half of patients. It is worth noting that fissures represent a heterogeneous cell population, exemplified by the
13
do not necessarily lead to ACS, as asymptomatic plaque fissure differential expression of CD14 and CD16. Human coronary
is a frequent event leading to plaque progression. Yonetsu et al. artery lesions contain macrophage subpopulations with different
using OCT found that about 15% of patients with SA presented gene-expression patterns. Patients with coronary atherosclerosis
+
+
7
with plaque fissure. A larger plaque burden, a thinner fibrous have higher numbers of circulating CD14 CD16 monocytes than
lo
hi
cap, and a smaller lumen size appear to predispose to thrombus healthy subjects. Finally, peak levels of CD14 CD16 monocytes
formation and ACS. 8 after acute MI correlate negatively with the recovery of left
Among the several inflammatory biomarkers tested in ACS, ventricular ejection fraction 6 months after MI. Noninvasive
levels of hs-CRP are typically elevated, in line with CRP’s high imaging technologies have now been developed to follow and
9
sensitivity and wide dynamic range. However, it is difficult to quantify subpopulations of monocytes and macrophages in vivo.
establish a cutoff at the present time. Whereas in primary preven- Monocytes accumulated within thrombi, obtained during
tion hs-CRP levels ≥2 mg/L (and even ≥1 mg/L) might be recom- primary PCIs, specifically overexpress Toll-like receptor 4 (TLR4),
mended, in ACS patients two different cutoffs have been suggested together with specific patterns of locally expressed chemokines
14
as clinically useful: an admission value ≥10 mg/L and a discharge and cytokines compared with circulating monocytes. TLR are
value ≥3 mg/L. These cutoffs, although confirmed in larger studies, key pattern-recognition receptors expressed by innate immunity
have not yet led to a general consensus. 4,10 cells that recognize a large number of pathogen-associated
Experimental studies have clarified the molecular mechanisms molecular patterns (PAMPs). Interestingly, Niessner et al. dem-
through which activation of inflammatory cells in the plaque can onstrated that interferon (IFN)-α produced by plasmacytoid
trigger thrombus formation. Inflammatory responses increase the dendritic cells in atherosclerotic plaques could enhance TLR4
fragility of the fibrous cap as well as the thrombogenic potential signaling by sensitizing these cells to lipopolysaccharide and other
of the plaque. The main mediators of inflammation-induced microbial molecules as well as to (modified) endogenous
activation of coagulation are proinflammatory cytokines. molecules, all abundantly present in the atherosclerotic lesion
Several studies have shown the importance of IL-6 in the initia- microenvironment. These sensitized antigen-presenting cells
tion of coagulation activation and the role of tumor necrosis (APCs) strongly upregulate the production of cytokines such as
factor-α (TNF-α) and IL-1 in the modulation of anticoagulant TNF-α, IL-12, IL-23, and matrix metalloproteinase-9 (MMP-9),
pathways. thus enhancing plaque instability. 15
It has been demonstrated that human platelets express
Widespread Coronary Inflammation functional TLRs capable of recognizing bacterial components.
In patients with ACS and systemic evidence of inflammation, TLR activation directly induces platelet aggregation and increased
widespread coronary inflammation is suggested by transcardiac platelet adhesion to collagen under flow conditions. Moreover,
neutrophil activation in the effluent of myocardial regions not stimulation of TLR, in particular TLR2, induces a significant
CHaPter 69 Inflammation and Atherothrombosis 939
Tolerogenic APC LTB4
Activated APC MPO
TLRs
PMN
IL-10;
IL-1, IL-2, TGF-β Ph-lipase
IL3, IL-12, O2 NADPH-Ox Lipo-Ox
IL-17 MPO
IL-23 MPO
IL-12 TGF-β -
Treg O2
Th0 Th1 H2O2 HOCL
T-cells
MMPs
IFN-γ, TNF-α TF Scavenger
Perforin, granzyme ROS receptor
TLRs
MIF
TNF-α MØ-foam
M-CSF cells
Adhesion IL-1, IL6,
molecules IL12, IL18
TLRs
ECs
Cytokines
PAF Chemokines
Cytokines PAI-1 P-selectin
Chemokines EDRF Collagen
TF ET1 sCD40L
Thrombin Heparin PLT
PAF4 TNF
SMCs Tryptase
Pro Active Mast cells
IL-1, IL-6, TF MMP MMP
TNF-α, IFN-γ
Chymase
Ang I Active
Ang I
FIG 69.3 Histological Features of Fissure-Prone Plaques. Both innate immunity and adaptive
immunity play a key role in the pathogenesis of coronary plaque instability. Multiple types of
inflammatory cells are present in atherosclerotic plaques. Macrophages (MØ) and mast cells
infiltrate the lesion and are particularly abundant in the shoulder region where the atheroma
grows and where the risk of plaque rupture is highest. T-cell infiltrates are always present in
atherosclerotic lesions. Such infiltrates are predominantly CD4 T cells, which recognize protein
antigens processed and presented by activated antigen-presenting cells (APCs). Regulatory T
cells (Tregs) maintain the homeostasis of cell subsets involved in adaptive immunity. In human
atherosclerotic lesions, Treg colocalize with interleukin-10 (IL-10) and transforming growth factor
(TGF)-β expression. TLR, Toll-like receptor; Ang, angiotensin I; EC, endothelial cell; EDRF,
endothelium-derived relaxing factor; ET1, endothelin 1; IFN, interferon; IL12R, IL-12 receptor;
LTB-4, leukotriene B-4; M-CSF, macrophage colony–stimulating factor; MMPs, metalloproteinases;
MØ, macrophage; MPO, myeloperoxidase; TF, tissue factor; PAF, platelet-activating factor; PAI,
plasminogen activator inhibitor; PLT, platelet; PMN, polymorphonuclear cell; ROS, reactive oxygen
species; sCD40L, soluble CD40 ligand; SMC, smooth muscle cell.
940 Part seven Organ-Specific Inflammatory Disease
increase in the interactions of platelets and leukocytes and in showing a marked increase in Th1 frequency and increased
the amplification of platelet-derived inflammatory signals. These expression of Th1-related effector molecules such as IFN-γ,
findings highlight the role of platelets as immunological cells, signal transducer and activator of transcription 4 (STAT4), and
20
critically participating in both inflammatory and thrombotic T-bet . Th1 cells are suspected of regulating the fragility of the
processes. Indeed, platelet TLR2 and related innate immune fibrous cap as well as the thrombogenic potential of the plaque.
transcripts have been associated with cardiovascular disease and IFN-γ can contribute to plaque destabilization in several ways:
its risk factors. Expression of TLR2 in megakaryocytes suggests by the recruitment and activation of macrophages in the ath-
that inflammatory processes, through TLR2 stimulation, can erosclerotic lesions; by reducing collagen synthesis; by increasing
increase megakaryocyte maturation and can modulate mega- the production of extracellular matrix–degrading proteins; and
karyocyte phenotypes, potentially influencing platelet function by activating APC. Furthermore, increased IFN-γ expression
and thrombosis. induces a positive feed-forward loop of Th1 induction sustaining
a proinflammatory state. When activated in the intima, Th1 cells
Activation of Adaptive Immunity produce proinflammatory cytokines and enhance the expression
In patients with ACS and systemic evidence of inflammation, the of CD40 ligand. Ligation of CD40 on APC by CD40 ligand
higher frequency of activated T cells in comparison to patients induces release of extracellular matrix–degrading metallopro-
with SA suggests that the sudden changes leading to coronary teinases and the expression of tissue factor, a key initiator of the
instability might be related to mechanisms involving T-cell immu- coagulation cascade.
nity. In particular, in ACS patients CD4 T-cell subpopulations
+
null
are dysregulated, and their abnormalities are associated with CD4 CD28 T Cells
+
null
worse outcomes, especially in patients with diabetes mellitus. 16-18 CD4 CD28 T cells are distinct from classic helper T cells in
ACS patients have a skewed T-cell differentiation oriented several aspects. This terminally differentiated subpopulation
toward aggressive effector phenotypes and defective regulatory shows an increased resistance to apoptosis and a wide range of
T cells, suggesting that the lymphocyte compartment fails to proinflammatory properties.
+
null
suppress excessive immune responses. Overall, such T-cell CD4 CD28 T cells are present preferentially in unstable
16
abnormalities characterize about half of ACS patients. In this ruptured atherosclerotic plaques, and their frequency significantly
subset of ACS patients, helper T-cell dysregulation might affect increases the risk of ACS, particularly in patients with diabetes. 16-18
+
null
the biological outcome of the immune response and contribute CD4 CD28 T cells from ACS patients show several abnormali-
to plaque destabilization through multiple damaging pathways ties such as the ability to mediate endothelial cytotoxicity by
(Fig. 69.3). triggering the NK stimulatory receptor KIR2DS2, killer Ig-like
T cells physiologically drive B-cell hypersomatic mutation, receptor 2DS2 (KIR2DS2) in the absence of T-cell receptor (TCR)
isotype switch, and affinity maturation in the germinal centers activation and higher levels of costimulatory receptors, e.g., OX40
of lymphoid organs and also in extranodal sites in autoimmune and 4–1BB.
19
diseases . Indeed, coronary atherosclerotic plaques obtained by
endoluminal directional atherectomy are sites of B lymphocyte Th17 Cells
proliferation in patients with ACS, strongly suggesting the local Th17 cells are characterized by the expression of retinoid orphan
presence of an activating or recruiting antigen in these lesions receptor (ROR)-γt, the master regulator transcription factor
(Table 69.3). responsible for the production of IL-17.
Although the precise role of IL-17 in atherosclerosis and ACS
T-helper 1 (Th1) Cells remains controversial, experimental studies in mice have
21
The importance of Th1 and IFN-γ in atherosclerosis progression provided direct evidence that IL-17 is predominantly proath-
and in plaque destabilization is confirmed by numerous studies erogenic. Indeed, in combination with IFN-γ, IL-17 induces a
proinflammatory response in vascular smooth muscle cells. On
the other hand, Th17 cells are involved in wound healing and
exert powerful fibrogenic activity. These cells activated in the
TABLE 69.3 Potential role of Infection in context of the atherosclerotic plaque promote the formation of
atherosclerosis and thrombosis thick collagen fibers that can resist the mechanical assault exerted
Infectious Organisms Implicated by hemodynamic forces. This is due to the capacity of the IL-17
Viruses to promote procollagen expression.
Herpes viruses (e.g., cytomegalovirus)
Bacteria Regulatory T Cells
Chlamydia pneumonia In atherosclerosis, the role of regulatory T cells (Treg) is well
Helicobacter pylori appreciated. Indeed, this T-cell subpopulation inhibits athero-
Porphyromonas gingivalis?
sclerosis development and progression by suppressing effector
Mechanism(s) by Which Infections May Contribute T-cell responses. A defective Treg compartment has been
to atherothrombosis demonstrated in the peripheral blood of ACS; these patients
Direct infection of the vascular wall with endothelial injury, show low levels of circulating Treg, a reduced suppressive efficiency
16
inflammatory cell recruitment, and activation (Chlamydia of Treg, and an increased Treg susceptibility to apoptosis. In a
pneumoniae, herpes virus, cytomegalovirus) small study, Treg have been identified as the major T-cell subset
Immune-mediated vascular injury through molecular mimicry in aspirated coronary thrombus adjacent to the culprit lesion
(Chlamydia pneumoniae) in patients with ACS, associated with a restricted TCR diversity
Remote infections with systemic activation of the inflammatory
response (Helicobacter pylori, Porphyromonas gingivalis) in thrombus-resident T cells; this suggests an increased antigen-
specific Treg redistribution between the peripheral blood and
CHaPter 69 Inflammation and Atherothrombosis 941
22
local sites of inflammation. Nevertheless, ACS patients have a 22 (PTPN22). This enzyme plays a key role in controlling the
lower induction of Treg after TCR stimulation with anti-CD3 intensity of the early TCR signal transduction acting on LCK and
23
23
and anti-CD28 antibodies. Notably, the defective TCR-induced on Zap70.
Treg generation is partially recovered 1 year after the index event,
suggesting a transient phenomenon present during the acute PLAQUE FISSURE WITHOUT SYSTEMIC
phase of the disease. Thus defects in the Treg compartment might INFLAMMATION
affect the plaque stability by impairing a balanced immune
response in atherosclerosis. Indeed, Treg have been implicated When plaque fissure occurs without systemic inflammatory activa-
in the inhibition of effector T cells, in the suppression of endo- tion, other mechanisms, including emotional and physical stress or
1
thelial and macrophage activation, and in the modulation of changes in plaque composition, may play a pathogenic role. The
cholesterol metabolism. ability of systemic stress to induce plaque fissure might be related
to sympathetic nervous system activation and catecholamine
B Cells release associated with increased heart rate, increased blood
The contribution of B cells in autoimmunity is well recognized. pressure, and coronary vasoconstriction. Besides the fissuring of
The function of B cells has been evaluated in various animal vulnerable plaque, these conditions favor platelet activation, hyper-
models of atherosclerosis; B1a cells and their secretion of IgM coagulability, and intense coronary microvascular constriction.
seem to mediate the protective effects of B cells, whereas B2 cells It has been demonstrated that the highest shear stress is present
are proatherogenic through modulation of T cell–dependent at the level of the shoulder region of the fibrous cap. Changes
mechanisms. in plaque composition may be another possible cause of plaque
Moreover, antibodies against several oxidation-specific epitopes fissure. Indeed local changes in pH, temperature, cholesterol
of low-density lipoprotein and other atherosclerosis-related saturation, and hydration promote cholesterol crystallization in
antigens are found in animals and humans, both in the circulation the lipid core associated with quick volume expansion, potentially
24
and in atherosclerotic plaques. The mechanisms by which these causing plaque fissure and thrombosis. These mechanisms may be
antibodies act remain unclear, and it is unresolved whether they amplified by crystallization of free cholesterol from erythrocyte
represent an epiphenomenon of chronic immune stimulation membranes when intraplaque hemorrhage occurs.
or a disease-specific phenomenon.
PLAQUE EROSION
TCR Signaling Alteration in ACS
The first step in lymphocyte activation is TCR binding of specific Plaque Erosion: Pathological Findings
peptides presented by APC. TCR triggering initiates a cascade Plaque erosion is associated with coronary instability in about
of phosphorylation events that culminate in the activation and one-third of patients. Eroded plaques are characterized by
nuclear translocation of transcription factors (Chapter 12). A thrombus formation at the site of a denuded fibrous atheroscle-
complex molecular coordination is required, including positive rotic plaque. Endothelial denudation leads to the exposure of
and negative feedback loops necessary to avoid lymphocyte hyper- the intima that often shows a pathological thickening and consists
reactivity and the breaking of immune tolerance. The proper predominantly of vascular smooth muscle cells and proteoglycans,
tuning of TCR signaling is critical also for T-cell differentiation. heavily glycosylated proteins able to form large complexes by
Indeed, in addition to the cytokine environment, the induction binding other proteoglycans, hyaluronan, and collagen. There
of different T-helper cell lineages is driven by TCR-mediated are no pathognomonic features to identify plaque erosion. An
signal strength. eroded plaque in a histological specimen is recognized when
CD4 T cells from ACS patients show enhanced response to serial sectioning of thrombosed arterial segments fails to reveal
TCR stimulation and have a lower setting of the T-cell activation plaque rupture. Compared with plaque fissure, which typically
threshold, attributable to enhanced amplification of proximal has a large lipid pool, plaque erosion shows intact internal and
TCR-mediated signals. 23,25 Intriguingly, some of these abnormali- external elastic laminas and a well-developed media (unlike
ties are confined to the acute phase of ACS, whereas others persist plaque rupture, where the internal lamina is often disrupted and
also during the stable phase of the disease, suggesting the existence the underlying media is thin and disorganized), rare calcifications,
26
of chronic lymphocyte hyperreactivity. and a lower grade of inflammation. There is still no agreement
The molecular TCR signaling alterations observed in ACS on the grade of luminal obstruction related to plaque erosion
include an increase in the positive activation signals, including because some groups have demonstrated that eroded plaques
higher accumulation of CD3 complexes and zeta-chain associated are less obstructive than ruptured plaques with thrombosis, and
26
protein kinase of 70 kD (Zap70) in the immunological synapse others report the opposite (Fig. 69.4).
during antigen presentation; higher early tyrosine phosphoryla- The detection of eroded plaques by OCT is based upon
6
tion after TCR stimulation; and a defective deactivation of the exclusion criteria. Similar to histological detection, OCT con-
lymphocyte-specific protein tyrosine kinase (LCK). On the other firmation of plaque erosion derives from the absence of fibrous
hand, ACS patients exhibit reduced activity of the inhibitory cap discontinuation after intraluminal thrombi aspiration. It is
molecular patterns such as reduced phosphorylation of Zap70 not always possible to obtain a proper distinction between fissured
at its inhibitory residue Tyr-292, a residue implicated in TCR and eroded plaque by imaging, and it is even more challenging
deactivation; lower expression of PECAM-1, a molecule implicated to distinguish erosion-prone plaques from stable plaques.
in downmodulation of T cell activity; and reduced activation
of CREB, a transcription factor believed to be particularly Mechanisms of Plaque Erosion
important for the generation and maintenance of Treg and for Several studies have highlighted the high frequency of ACS
25
IL-2 and IL-10 production. Finally, ACS patients show enhanced associated with plaque erosion in women and in young persons,
1
expression of the protein tyrosine phosphatase non–receptor type mostly after stressful events and possibly reflecting acute changes
942 Part seven Organ-Specific Inflammatory Disease
Pam3 E-selectin
HSVEC LTA ICAM Caspase 3
IL-8
+ ROS Caspase 7 Early
TLR 4h 24h stimulus
2
VE-cadherin
PMN
MPO/MMP
Hyaluronan Exposure Apoptosis
Late stimulus
CD44
NET
Thrombus
FIG 69.4 A Hypothetical Model of Plaque Erosion. Toll-like receptor (TLR) 2 stimulation on
endothelial cells (HSVEC [human saphenous vein endothelial cells]) with Pam3 or lipoteichoic
acid (LTA) has been reported to induce endothelial activation and apoptosis, as suggested by
increased levels of adhesion molecules (E-selectin, ICAM), interleukin-8, and caspases -3 and -7.
This process is markedly potentiated but not necessarily initiated by polymorphonuclear neutrophil
(PMN) and leads to endothelial damage and extracellular matrix (ECM) exposure. Hyaluronic acid,
a component of ECM, is a ligand for TLR2 and for the receptor CD44 and might be involved in
the propagation of the inflammatory process. In humans, eroded plaques typically harbor abundant
hyaluronan and proteoglycans. Thus hyaluronic acid could be considered a relevant TLR2 agonist.
Also, products from infectious microorganisms may operate to promote atherothrombosis through
this mechanism. MPO, myeloperoxidase; MMP, metalloproteinase; NET, neutrophil extracellular
trap; ICAM, intercellular adhesion molecule; ROS, reactive oxygen species.
28
in local hemodynamics and atherosclerotic artery. Animal models activators for TLR2. Intense immunostaining for hyaluronan
have demonstrated that local vasoconstriction that precedes and its receptor, CD44, has been detected along the interface
myocardial ischemia is occasionally accompanied by intracoronary between luminal thrombus and eroded plaque compared with
28
thrombosis with endothelial lesions resembling human plaque fissured or stable plaque. These data led to the intriguing
erosion. A role of the innate immune system in this process has hypothesis that the accumulation of hyaluronan along the plaque
also been proposed, specifically a possible involvement of may be involved, through CD44 activation, in the promotion of
neutrophils. Coculture of neutrophils with endothelial cells endothelial discontinuity, thrombus formation, and leukocyte
induced endothelial injury and triggered endothelial cell apoptosis. accumulation. The ligation of TLR2 has been shown to result
Plasma from patients with eroded culprit plaques exhibited in inflammation and endothelial apoptosis in a process that could
elevated systemic myeloperoxidase (MPO) levels, produced be markedly potentiated but not necessarily initiated by poly-
primarily by PMNs, compared with levels in patients showing morphonuclear leukocytes. A “two-step model” has been proposed
plaque fissure. Moreover, in postmortem coronary specimens, in which the first hit derives from TLR2 activation and leads to
eroded plaque showed a much higher density of MPO-positive an initial endothelial injury, with subsequent apoptosis and
6
cells in luminal thrombi compared with fissured plaque. Endo- desquamation; the second hit is mediated by neutrophil recruit-
thelial cells overlying atherosclerotic lesions abundantly express ment, with propagation of the local process and amplification
29
27
the pattern-recognition receptor TLR2. TLR2 has been localized of endothelial damage. In humans, eroded plaques typically
mostly in areas of disturbed blood flow, and animal models have harbor abundant hyaluronan and proteoglycans, and TLR2 ligands
shown that the inhibition of this receptor reduces endothelial typically include both endogenous and exogenous gram-positive
dysfunction by low shear stress. In lesions prone to erosion, derived hyaluronan. Thus it has been proposed that hyaluronic
lipoproteins and proteoglycans could serve as endogenous acid could be considered a disease-relevant TLR2 agonist, and
CHaPter 69 Inflammation and Atherothrombosis 943
that endogenous as well as infectious factors may operate to CLINICAL PERSPECTIVE
promote atherothrombosis through this mechanism.
Endothelial erosion occurs on plaques scarcely calcified, less Precision medicine does not generally imply the creation of drugs
prone to expansive remodeling, and only sparsely inflamed. or medical devices that are unique to a single patient. Instead,
However, neutrophil infiltration that typically follows plaque precision medicine signifies the ability to classify individuals into
erosion is considered a hallmark of this distinct morphology of subpopulations that differ in their susceptibility to a particular
vulnerable plaques. No specific morphological features have been disease, in the biology and/or prognosis of those diseases they
identified to distinguish eroded plaques from stable plaques and may develop, or in their response to a specific treatment. Pre-
rupture-prone plaques, and both the limitation of imaging ventive or therapeutic interventions can then be concentrated
techniques and the relative lack of animal models have hampered on those who will benefit, sparing expense and side effects for
progress in this field. those who will not. Indeed, coronary thrombosis is the final
common pathway leading to ACS. More potent antithrombotic
regimens have recently been found to increase the risk of major
KeY COnCePts bleedings, which are associated in turn with a higher risk of
epidemiology of Ischemic Heart Disease mortality. Although the early outcome of ACS has consider-
• Main cause of morbidity and mortality ably improved in the past decade, cardiovascular diseases still
• Recurrence of ACS eventually leads to the pandemics of heart failure represent the main cause of morbidity and mortality overall.
and sudden cardiac death The rate of death, MI, and recurrent ACS at 1-year follow-up in
• Need for a reappraisal of the mechanisms responsible for coronary contemporary NSTE-ACS registries is still very high, approaching
instability and for innovative preventive and therapeutic strategies about 25%. Furthermore, recurrent ACS heralds a progressive
30
impairment of myocardial function leading to chronic heart
Current Concepts on atherosclerosis and Chronic Inflammation failure. Importantly, ischemic heart disease is by far the most
• Atherosclerosis is a chronic non-resolving inflammatory disease important cause of heart failure and thus a public health problem
• Atherosclerotic plaques can remain stable indefinitely
• The mechanisms responsible for coronary instability are multiple of pandemic proportions. Thus the best prevention of heart failure
is the prevention of recurrent episodes of coronary instability
Pathogenic Classification of acute Coronary syndromes (Table 69.4).
• Plaque fissure with systemic inflammation
• Plaque fissure without systemic inflammation
• Plaque erosion CLInICaL reLevanCe
• Functional alterations of coronary circulation (epicardial or microvascular
spasm) • Different mechanisms and triggers are involved in ACS. The pathogenic
classification of ACS might be a useful tool to select the best approach
Main Feature of Inflammation and Immunity associated With for different patients
Plaque Fissure • Histological studies have shown that ACS could be initiated by different
types of unstable plaque
• Often associated with systemic inflammation • Plaque fissure is strictly associated with systemic and coronary
• Widespread coronary inflammation inflammation, with an altered cross-talk between innate and adaptive
• Innate immunity activation (monocytes, neutrophils, Pattern Recognition immunity leading to the unbalance between pro- and anti-inflammatory
Receptors) stimuli
• Adaptive immunity alterations (unbalances between pro-inflammatory • Plaque erosion rely on less clear mechanisms, however an inflammatory
and anti-inflammatory activity)
trigger might be also involved, with different triggers as compared
with plaque fissure, such as hyaluronan exposure and PMN
Main Feature of Inflammation and Immunity associated With recruitment.
Plaque erosion
• Neutrophil accumulation
• Hyaluronan accumulation
• TLR2 activation Plaque Fissure With Systemic Inflammation
The experience gained in the diagnosis, risk stratification, and
management of chronic inflammatory diseases may provide
FUNCTIONAL ALTERATIONS OF important clues to the management of atherothrombosis. Exten-
CORONARY CIRCULATION sive studies regarding helper T-cell subset dysregulation in ACS
strongly support the notion that adaptive immunity is critically
Epicardial coronary vasospasm is a possible cause of ACS when involved in the disease process. Investigating the mechanisms
coronary angiography fails to demonstrate the presence of an underlying T-cell dysregulation is pivotal to identifying new clini-
1
obstructive atherosclerotic plaque. The mechanisms underlying cal biomarkers and potential therapeutic targets in the subset of
coronary spasm are multifold and may involve enhanced Rho ACS patients in whom a T cell–dependent inflammatory outburst
kinase activity in smooth muscle cells. is the likely cause of coronary instability. In this subset of ACS
Vasoconstriction causing ACS can be located also at the patients, raised levels of hs-CRP or of other soluble markers of
4,10
microvascular level. In particular, intense coronary microvascular inflammation are associated with a worse outcome. A specific
vasoconstriction plays an important role in the pathogenesis of adaptive immune system signature proved to be more predictive
Takotsubo syndrome, which is diagnosed by ischemic pain at than biomarkers in the identification of homogeneous subsets
16
rest, ischemic ST-segment changes, and rise in cardiac enzymes. of patients at higher risk for acute coronary event recurrence.
The syndrome also is characterized by a regional akinesia that A change of focus from soluble markers of inflammation to
more frequently affects distal myocardial regions but also is markers of adaptive immunity regulation, such as the molecules
associated with hypercontractility of the remaining regions. involved in TCR signaling, might be more rewarding.
944 Part seven Organ-Specific Inflammatory Disease
TABLE 69.4 Pathogenical Mechanisms, Diagnosis, and Potential tailored therapy of acute
Coronary syndromes
Mechanism Diagnosis Potential therapeutic target
Plaque fissure with 1. Innate immunity Hs-CRP levels Immunosuppression (cyclosporine, tacrolimus,
systemic inflammation Early neutrophil activation T-cell phenotyping sirolimus, AZT, imatinib)
Inflammatory macrophages Functional imaging TCR signaling regulation (synthetic CD31-
Platelet activation (TLRs) derived peptide, PTPN22 inhibitor)
2. Adaptive immunity IL-1β antagonists (anakinra, canakinumab,
null
+
CD4 CD28 T-cell expansion rilonacept)
Treg imbalance Treg expansion, anti-CD3-Ab (mice)
Th17 cells Vaccines
B cells High-dose statins
Plaque fissure without 1. Sympathetic nervous system activation Anatomical imaging Statins
systemic inflammation 2. Changes in plaque composition PLA 2 inhibitors
Enhancement of cholesterol Efflux/impairment
of foam cells formation (3-
hydroxyanthranilic acid)
Plaque erosion 1. PMN producing MPO MPO levels Antithrombotic drugs
2. Hyaluronan/CD44 interaction Functional imaging
3. TLR2 activation and endothelial injury
4. Acute local hemodynamic changes
Functional alterations 1. Epicardial coronary spasm (enhanced Functional tests of vasomotility Nitrates
Rho kinase activity) Rho kinase activity Calcium antagonists
2. Microvascular spasm Rho kinase inhibitors
AZT, azathioprine; Hs-CRP, high-sensitivity C-reactive protein; IL-1β, interleukin-1β; MMPs, matrix metalloproteinases; MPO, myeloperoxidase; PLA2, phospholipase A2TCR; PMN,
polymorphonuclear neutrophil; PTPN22, protein tyrosine phosphatase non–receptor type 22; TCR, T-cell receptor; Th17, T-helper cell-17; TLRs, toll-like receptors.
An unmet need in this patient subset is a specific antiinflam- a thinner cap compared with plaque fissure occurring at rest,
matory treatment. 31,32 Indeed, TCR activation signaling offers indicating greater susceptibility to biomechanical forces. The
several targets for immunosuppressive therapy such as cyclo- development of micro-OCT that enables imaging of coronary
sporine, tacrolimus, sirolimus, azathioprine, and imatinib artery microstructure on a scale comparable to that of histopathol-
mesylate. These drugs prevent T-cell activation and reduce ogy might shed some new light on the role played by cholesterol
hyperreactivity of the adaptive immune system and development crystallization. Inflammasome activation due to cholesterol
of autoimmunity. A synthetic CD31-derived peptide, able to crystals has been discussed as a potential mechanism.
engage a truncated extracellular CD31 fragment expressed by T
cells that apparently lack CD31, has an immunosuppressive effect Plaque Erosion
in vivo through restoration of the CD31 inhibitory pathway. The In plaque erosion, MPO is an important bystander and might
development of a novel series of inhibitors of PTPN22 might even play a pathogenic role. Molecular imaging techniques can
contribute to a better understanding of the role of this phosphatase visualize MPO in atherosclerotic plaques in carotid arteries;
in the immune dysregulation of ACS patients. these methods are more difficult, however, in coronary circula-
Another intervention target might be restoring the balance tion. Elevated plasma concentration of MPO might represent
between effector T cells and Treg cells. Adoptive transfer of ex an important biomarker for the identification of this subset
6
vivo expanded Treg might be considered. Of note, in mice of patients. In patients with plaque erosion, the mechanism
anti-CD3 antibody treatment induced rapid regression of of inflammation is probably an intense local thrombogenic
established atherosclerosis by reducing CD4 T cells and increasing stimulus. Thus potent antithrombotic treatment, based perhaps
33
the proportion of Treg. Additionally, it has been shown that on double antiaggregation and an oral anticoagulant, might be
the tryptophan metabolite 3-hydroxyanthranilic acid has immune the treatment of choice, but this approach must be tested in
regulatory properties that can be used to decrease atherosclerosis prospective studies.
in mice by regulating T cell–dependent inflammation and lowering
plasma lipids. Finally, the identification of antigens that trigger Functional Alterations of Coronary Circulation
adaptive immunity may open the way for specific vaccinations. Clinical history and 24- to 72-hr ambulatory ECG monitoring
Notably, strengthening antiviral immunity in at-risk patients, are usually sufficient to achieve the diagnosis of vasospastic
e.g., by vaccination against influenza, has been associated with angina, whereas the use of provocative tests of coronary artery
reduction in cardiovascular events, demonstrating the value of spasm (e.g., intravenous ergonovine, intracoronary ergonovine,
host protection through health maintenance. 34 or acetylcholine administration) is required in about 10% of
patients. Rho kinase activity in circulating neutrophils is increased
Plaque Fissure Without Systemic Inflammation and might represent a useful biomarker for diagnosis and disease
Clinical history of extreme emotional disturbance or intense activity assessment. Although nitrates and calcium antagonists
physical exertion might help to identify this subset of patients. are helpful in patients with vasospastic angina, further efforts
Anatomical (more than functional) features of the atherosclerotic are needed to identify the molecular alterations responsible for
plaque are important in determining coronary instability. Thus smooth muscle cell hyperreactivity because a sizable proportion
noninvasive imaging of stress-related plaque fissure might reveal of these patients are refractory to standard doses of vasodilator.
CHaPter 69 Inflammation and Atherothrombosis 945
Similarly, further efforts are warranted to identify a therapeutic 8. Bourantas CV, Garcia-Garcia HM, Farooq V, et al. Clinical and
target in Takotsubo syndrome. angiographic characteristics of patients likely to have vulnerable plaques:
analysis from the PROSPECT study. JACC Cardiovasc Imaging
2013;6(12):1263–72.
CONCLUSION 9. Casas JP, Shah T, Hingorani AD, et al. C-reactive protein and
coronary heart disease: a critical review. J Intern Med 2008;264:
As observed above, inflammation plays a detrimental role in the 295–314.
setting of ACS not only in determining plaque instability, but 10. Biasucci LM, Koenig W, Mair J, et al. How to use C-reactive protein in
also in cardiac remodeling after myocardial necrosis and in acute coronary care. Eur Heart J 2013;34:3687–90.
PCI-related myocardial injury. The different mechanisms con- 11. Buffon A, Biasucci LM, Liuzzo G, et al. Widespread coronary
tributing to the inflammatory outbursts observed in ACS might inflammation in unstable angina. N Engl J Med 2002;347:5–12.
need different forms of antiinflammatory treatment. 12. Narducci ML, Grasselli A, Biasucci LM, et al. High telomerase activity in
In addition to specific interventions targeting adaptive neutrophils from unstable coronary plaques. J Am Coll Cardiol
immunity in plaque fissure and systemic markers of inflammation 2007;50:2369–74.
as discussed above, IL-1 blockade might specifically address 13. Wyss CA, Neidhart M, Altwegg L, et al. Cellular actors, Toll-like receptors,
inflammation due to myocardial necrosis and prove to be useful and local cytokine profile in acute coronary syndromes. Eur Heart J
2010;31:1457–69.
in ventricular remodeling after myocardial necrosis, as suggested 14. Liuzzo G, Montone RA, Gabriele M, et al. Identification of unique
by the results of small pilot studies in STEMI patients. 31,32,34 adaptive immune system signature in acute coronary syndromes.
Finally, IL-6 blockade might prevent inflammation associated Int J Cardiol 2013;168:564–7.
with distal embolization in the setting of PCI in NSTEMI, resulting 15. Libby P, Nahrendorf M, Pittet MJ, et al. Diversity of denizens of the
in less myocardial injury. 34 atherosclerotic plaque: not all monocytes are created equal. Circulation
2008;117:3168–70.
16. Niessner A, Shin MS, Pryshchep O, et al. Synergistic proinflammatory
On tHe HOrIZOn effects of the antiviral cytokine interferon-alpha and Toll-like receptor
4 ligands in the atherosclerotic plaque. Circulation 2007;116:
Translational research is needed: 2043–52.
• To improve diagnostic criteria of vulnerable plaque 17. Liuzzo G, Biasucci LM, Trotta G, et al. Unusual CD4+CD28null T
• To find novel predictive markers of plaque instability lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol
• To find specific triggers linked to different types of unstable plaque 2007;50:1450–8.
• To clarify the role of inflammation in plaque destabilization 18. Giubilato S, Liuzzo G, Brugaletta S, et al. Expansion of CD4+CD28null
• To evaluate alternative treatments and drug targets to prevent and T-lymphocytes in diabetic patients: exploring new pathogenetic
treat plaque instability mechanisms of increased cardiovascular risk in diabetes mellitus. Eur
Toll-like receptor (TLR) antagonists Heart J 2011;32:1214–26.
Repair T-cell signaling abnormalities and CD31 signaling potentiation 19. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev
Restore Treg number and activity Immunol 2012;30:221–41.
Target myeloperoxidase (MPO) in plaque erosion 20. Liuzzo G, Vallejo AN, Kopecky SL, et al. Molecular fingerprint of
interferon-gamma signalling in unstable angina. Circulation
2001;103:1509–14.
21. Liuzzo G, Trotta F, Pedicino D. Interleukin-17 in atherosclerosis and
Please check your eBook at https://expertconsult.inkling.com/ cardiovascular disease: the good, the bad, and the unknown. Eur Heart J
for self-assessment questions. See inside cover for registration 2013;34:556–9.
details. 22. Klingenberg R, Brokopp CE, Grivès A, et al. Clonal restriction and
predominance of regulatory T cells in coronary thrombi of patients with
acute coronary syndromes. Eur Heart J 2015;36:1041–8.
REFERENCES 23. Flego D, Severino A, Trotta F, et al. Increased PTPN22 expression and
defective CREB activation impair regulatory T-cell differentiation in
1. Crea F, Liuzzo G. Pathogenesis of acute coronary syndromes. J Am Coll non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol
Cardiol 2013;61:1–11. 2015;65:1175–86.
2. Vergallo R, Papafaklis MI, Yonetsu T, et al. Endothelial shear stress and 24. Biasucci LM, Liuzzo G, Ciervo A, et al. Antibody response to chlamydial
coronary plaque characteristics in humans: combined frequency-domain heat shock protein 60 is strongly associated with acute coronary
optical coherence tomography and computational fluid dynamics study. syndromes. Circulation 2003;107:3015–17.
Circ Cardiovasc Imaging 2014;7(6):905–11. 25. Flego D, Severino A, Trotta F, et al. Altered CD31 expression and activity
3. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating in helper T cells of acute coronary syndrome patients. Basic Res Cardiol
the biology of atherosclerosis. Nature 2011;473:317–25. 2015;109:448.
4. Liuzzo G, Biasucci LM, Gallimore JR. The prognostic value of C-reactive 26. Virmani R, Kolodgie FD, Burke AP, et al. Lessons from sudden coronary
protein and serum amyloid a protein in severe unstable angina. death: a comprehensive morphological classification scheme for
N Engl J Med 1994;331:417–24. atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:
5. Ong P, Athanasiadis A, Borgulya G, et al. 3-year follow-up of patients 1262–75.
with coronary artery spasm as cause of acute coronary syndrome: the 27. Mullick AE, Soldau K, Kiosses WB, et al. Increased endothelial expression
CASPAR (coronary artery spasm in patients with acute coronary of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early
syndrome) study follow-up. J Am Coll Cardiol 2011;57:147–52. atherogenic events. J Exp Med 2008;205:373–83.
6. Niccoli G, Liuzzo G, Montone RA, et al. Advances in mechanisms, 28. Kolodgie FD, Burke AP, Farb A, et al. Differential accumulation of
imaging and management of the unstable plaque. Atherosclerosis proteoglycans and hyaluronan in culprit lesions: insights into plaque
2014;233:467–77. erosion. Arterioscler Thromb Vasc Biol 2002;22:1642e8.
7. Yonetsu T, Kakuta T, Lee T, et al. In vivo critical fibrous cap thickness for 29. Quillard T, Araujo HA, Franck G, et al. TLR2 and neutrophils potentiate
rupture-prone coronary plaques assessed by optical coherence endothelial stress, apoptosis and detachment: implications for superficial
tomography. Eur Heart J 2011;32:1251e9. erosion. Eur Heart J 2015;36:1394–404.
946 Part seven Organ-Specific Inflammatory Disease
30. Roffi M, Patrono C, Collet JP, et al. ESC Guidelines for the management 32. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular
of acute coronary syndromes in patients presenting without persistent disease. Eur Heart J 2014;35:1782–91.
ST-segment elevation: Task Force for the Management of Acute Coronary 33. Kita T, Yamashita T, Sasaki N, et al. Regression of atherosclerosis with
Syndromes in Patients Presenting without Persistent ST-Segment anti-CD3 antibody via augmenting a regulatory T-cell response in mice.
Elevation of the European Society of Cardiology (ESC). Eur Heart J Cardiovasc Res 2014;102:107–17.
2016;37:267–315. 34. Crea F, Liuzzo G. Anti-inflammatory treatment of acute coronary
31. Della Bona R, Liuzzo G, Pedicino D, et al. Anti-inflammatory treatment syndromes: the need for precision medicine. Eur Heart J
of acute coronary syndromes. Curr Pharm Des 2011;17:4172–89. 2016;37:2414–16.
CHaPter 69 Inflammation and Atherothrombosis 946.e1
MUL t IPL e -CHOIC e QU est IO ns
1. Indicate which of the following represents the correct timeline 2. Which of the following represents a recognized mechanism
in the natural history of atherosclerosis: involved in plaque instability?
A. Subendothelial retention of lipoproteins and flow-mediated A. Increase in regulatory T cells (Tregs) around the plaque
inflammatory changes → endothelial dysfunction → B. Widespread coronary inflammation
self-maintaining inflammatory state → fatty streak → C. Smooth muscle cells hyperreactivity
atheroma→ fibroatheroma D. Metabolic disturbances
B. Fatty streak → endothelial dysfunction → self-maintaining 3. The mechanisms involved in plaque erosion are still poorly
inflammatory state → subendothelial retention of lipo- understood; according to recent experimental evidence, which
proteins and flow-mediated inflammatory changes → of the following seems to be the most probable trigger involved
atheroma→ fibroatheroma in endothelial erosion?
C. Fibroatheroma → endothelial dysfunction → fatty streak A. Inflammasome activation through cholesterol crystals inside
→ self-maintaining inflammatory state → subendothelial the plaque
retention of lipoproteins and flow-mediated inflammatory B. Coronary artery dissection
changes → atheroma C. Fibrous cap rupture
D. Self-maintaining inflammatory state → atheroma → D. Toll-like receptor (TLR) activation, extracellular matrix
fibroatheroma → endothelial dysfunction → fatty streak and hyaluronan exposure, neutrophil recruitment
→ subendothelial retention of lipoproteins and flow-
mediated inflammatory changes
70
Autoimmune Thyroid Diseases
Anna L. Mitchell, Simon H.S. Pearce
Autoimmune thyroid disorders are common, and, indeed, as a study estimated that about 80% of the propensity to develop
3
group, they are the most prevalent autoimmune disorders in GD is attributable to genetic factors. Further evidence for the
humans. Despite many common underlying features, such as a heritability of GD comes from the observation that it clusters
marked female preponderance, shared susceptibility alleles, and within families. Up to onequarter of individuals with GD
common autoantigens, Graves disease and autoimmune hypo have a firstdegree relative with the condition or with another
thyroidism have contrasting clinical characteristics. Over recent autoimmune thyroid disease, such as autoimmune hypothyroid
4
years, our knowledge about the underlying pathogenesis has ism. Should an individual have a sibling with GD, it is estimated
increased as a result of advances in human genomics, molecular that the relative risk (λ s ) of that individual developing GD is
immunology, and the availability of murine models of disease. around 10, which is comparable with that of other heritable
Novel therapies based on this increased understanding are now autoimmune conditions, such as type 1 diabetes, which has a
emerging. λ s of 15.
A number of genetic loci have been shown to contribute
to GD susceptibility (Fig. 70.1). These genes encode proteins
KEY CONCEPTS in biological pathways that regulate immune system activity
Classification of Autoimmune Thyroid Disease or thyroid biology. The major histocompatibility complex
4,5
(MHC) region on chromosome 6p21 has long been associated
Autoimmune hyperthyroidism Graves disease with multiple autoimmune conditions. Human leukocyte antigen
Autoimmune thyroiditis Hashimoto thyroiditis (HLA) genes found within the MHC region play a vital role in
Atrophic thyroiditis
Postpartum thyroiditis pathogen and selfpeptide recognition and therefore have a clear
role in immunity and in establishing and maintaining immune
tolerance (Chapter 5).
GRAVES HYPERTHYROIDISM In European populations, the primary association between
MHC and GD is with alleles of the class II MHC genes. The
Graves disease (GD) is a common autoimmune condition that HLADR3 allele is detected twice as frequently in subjects with GD
accounts for the majority of cases of hyperthyroidism in the as in healthy controls (i.e., 50% of GD subjects vs 25% of controls).
developed world. Its pathogenesis is unique among the auto At the protein level, neutral amino acids alanine or glutamine are
immune endocrinopathies because a key feature is the presence substituted for positively charged arginine at position 74 in the
of stimulating autoantibodies directed against the thyrotropin HLADR peptidebinding pocket, which is thought to alter the
(thyroidstimulating hormone [TSH]) receptor, which mimic bindingpocket configuration, more readily allowing selfpeptides
5
the action of TSH, a native hormone produced in the pituitary, to enter the antigen binding site. Importantly, 50% of individuals
to drive thyroid overactivity. Interestingly, thyroid dysfunction with GD do not have the HLA-DR3 allele, implying that there
is commonly associated with other extrathyroidal manifestations is unlikely to be a single antigenic epitope responsible for GD.
of GD, the most common being Graves ophthalmopathy (GO). The cytotoxic T lymphocyte antigen4 (CTLA4) gene (chro
mosome 2q33) encodes a costimulatory molecule expressed on
Epidemiology the surface of activated T cells, which plays a pivotal role in
GD is one of the most common autoimmune diseases, with a downregulating Tcell responses and in checking Tcell acti
prevalence of approximately 1% in women in the developed vation, emphasizing the contribution of inhibitory signals in
1
world. It is more common in iodinesufficient countries, where setting immune response thresholds (Chapter 18). The CT60
2
it accounts for 60–90% of cases of hyperthyroidism. GD is seven single nucleotide polymorphism (SNP) downstream from the
times more common in women than in men and may affect 3’ untranslated region (3’UTR) was found to influence GD
individuals at any age; however, the peak incidence occurs between susceptibility (odds ratio [OR] 1.5) and has been suggested as
6
the ages of 35 and 40 years. a possible etiological variant ; however, the functional effects
of this variant remain poorly defined and contributions from
Etiology other variants, such as at codon 17 in the CTLA4 signal peptide
GD is a complex genetic condition, implying that environmental remain likely. About 50% of individuals from healthy European
stimuli precipitate disease in genetically predisposed individuals populations carry the autoimmune “susceptible” CTLA4 haplo
who harbor multiple susceptibility alleles. A large Danish twin type; therefore other important factors are clearly at play. CTLA4
947
948 ParT SEvEN Organ-Specific Inflammatory Disease
PTPN22 IFIH1 SCGB3A2 TG CD25 CD40
FCRL3 CTLA4 MHC PD-L1 TSH-R BACH2
1 2 3 4 5 6 7 8 9 10111213141516171819202122X Y
FIG 70.1 Schematic diagram to illustrate the loci that have been associated with Graves disease
to date. Each locus is shown on its respective chromosome, with chromosome 1 depicted on
the left and chromosome Y on the right.
polymorphisms also contribute to susceptibility to type 1 diabetes, including noncoding or microRNAs (miRNAs), and/or epigenetic
autoimmune adrenal insufficiency, celiac disease, and several factors.
other autoimmune conditions. GD is one of the few autoimmune conditions for which links
8
The protein tyrosine phosphatase, non–receptor type 22 to environmental factors have been definitively established.
(PTPN22) gene on chromosome 1p13 encodes the lymphoid Iodine is one of the most common precipitants of thyroid
tyrosine phosphatase (LYP) molecule, which, like CTLA4, is dysfunction. With regard to GD, more cases are observed in
involved in the regulation of Tcell activation. In GD, a coding iodinesufficient areas. A study of individuals in Iceland, where
variant (R620W) was found more frequently in Caucasians with iodine intake is high, and agematched individuals in East
7
GD than in controls (13 vs 7% respectively, OR 1.8). This variant Jutland, Denmark, where iodine intake is low, showed that the
results in a shortlived protein product, which is believed to alter incidence of GD was more than double in the higher iodine
Tcell receptor signaling compared with the wildtype protein. environment. 2
The PTPN22*620 W variant is very rare in nonCaucasian Cigarette smoking also influences GD susceptibility and
populations, but different PTPN22 alleles have been associated severity, in particular of GO. Metaanalysis of eight studies
with autoimmunity in Asian cohorts. showed the OR for developing GD was 3.3 for current smokers
9
Products of several other genes involved in immunoregulation compared with that for lifelong nonsmokers. The same study
have been demonstrated to have allelic variants associated with also revealed that current smokers are more likely to develop
GD, including CD25, CD40, PDL1, IFIH1, BACH2, SCGB3A2, GO compared with nonsmokers (OR 4.4). The mechanism for
and FCRL3. In addition to these variants in immune regulatory this interaction remains to be fully elucidated; however, cigarette
pathways, loci specific to GD have been identified on the basis smoke extract has been shown, in vitro, to stimulate adipogenesis
of known thyroid pathophysiology. The gene encoding the TSH and glycosaminoglycans (GAGs) production by orbital fibroblasts,
receptor (TSHR) on chromosome 14q31 is an obvious candidate which accumulate in the orbital tissues in GO. 10
for GD, as the TSHR is directly stimulated by autoantibodies in Stress appears to influence both GD disease onset and clinical
affected individuals. Although initial studies reported conflict course. In one study, individuals with GD retrospectively reported
ing results, a definite association between a number of SNPs in more negative life events in the preceding year compared with
11
intron 1 of the TSHR gene and GD has now been confirmed in matched controls. This finding is replicated even when a group
5
Caucasians. The mechanism by which these intronic SNPs confer of “nonautoimmune” individuals with hyperthyroidism are
disease susceptibility is unknown. Another GD candidate is the used as controls, suggesting that stress is truly a precipitant for
thyroglobulin (TG) gene (8q24). This encodes the thyroglobulin autoimmune GD. 12
Tg protein, the precursor for the thyroid hormones triiodothy Changes in immune system function appear to influence the
ronine (T 3 ) and thyroxine (T 4 ). SNPs in the TG gene have been onset of GD. During pregnancy, which is a relatively immunosup
associated with GD in some Caucasian cohorts, and an epistatic pressed state, hyperthyroid GD is often mild and can be managed
interaction between a SNP in TG exon 33 and HLADR has been with smaller doses of antithyroid drugs. In some cases, it remits
suggested. This interesting interaction has raised the possibility entirely, allowing the individual to stop medication in the short
that Tg polymorphisms predispose to GD by modulating Tg term. However, in the postpartum period, when the immune
peptide presentation by antigenpresenting cells on HLA class system normalizes, there is typically worsening or relapse of GD.
II molecules to T cells. A similar phenomenon is seen in individuals who have been
Despite years of research into the genetic etiology of GD, significantly immunosuppressed and then have recovered. For
30–40% of the inherited susceptibility has yet to be accounted example, newonset GD has been reported in people who have
for. This “hidden” heredity is a common theme in genetically been successfully treated with highly active antiretroviral therapy
complex traits, but it is likely to be owing to rare genomic (HAART) for human immunodeficiency virus (HIV) infection.
variants, polymorphisms in regulatory DNA sequences, During treatment, as the immune system recovers, immune
CHaPTEr 70 Autoimmune Thyroid Diseases 949
N
LRRs
α/A subunit
Cleaved
region (residues
~316–366)
FIG 70.2 Diffuse lymphocyte infiltrate and thyrocyte hyperplasia
in a patient with Graves disease.
activation increases. T cells are exposed to thyroid antigens,
resulting in an autoimmune response at the time of immune Plasma membrane
13
reconstitution. A similar phenomenon has been seen in indi
viduals with multiple sclerosis (MS) treated with alemtuzumab, β/B subunit
the lymphocytedepleting antiCD52 antibody. An alternative
explanation is the weakening of physiological antiinflammatory
pathways, which unleashes the immune system. As more novel
biological agents become available, this phenomenon is likely
to become more common.
C
KEY CONCEPTS
Environmental Factors Known to Influence TMD
Graves Disease Susceptibility FIG 70.3 Structure of the thyroid-stimulating hormone receptor
(TSH-R). (Courtesy of R. Latif; adapted from Davies TF, Ando
• Smoking T, Lin RY, et al. Thyrotropin receptor-associated diseases:
• Iodine
• Stress from adenomata to Graves’ disease. J Clin Invest 2005;115:
• Immune system reconstitution states 1972–83.)
• Post-partum state
• Successful treatment of human immunodeficiency virus (HIV) with
highly active antiretroviral therapy (HAART)
• T-cell depletion therapy (e.g., alemtuzumab) in these infants, these autoantibodies are not sufficient, per se,
• Infections (e.g., hepatitis C) to result in the persistent thyroid autoreactivity of true GD.
TSHR antibodies are classically immunoglobulin G1 (IgG1)
subclass and target an epitope in the aminoterminal region of the
Immunopathogenesis leucinerich repeat motif in the extracellular domain of the TSHR
16
Histologically, the thyroid in GD is characterized by a diffuse (Fig. 70.3). When the autoantibody binds to the TSHR, this
lymphocytic infiltrate, consisting of both T and B cells, associated activates intracellular G proteins, which, in turn, induce transcrip
with thyrocyte hyperplasia (Fig. 70.2). Although T cells play a tion of genes, such as TPO and TG, via the cyclic adenosine
major role in inflammatory cell recruitment, cytokine secretion, monophosphate (cAMP) and phospholipaseC pathways. This
antigen recognition, and thyrocyte damage, infiltrating B cells results in thyrocyte hyperplasia and increased thyroid hormone
also produce antibodies, including those that drive hyperthyroid synthesis. The TSHR antibody–induced expression of TPO and
ism. The major autoantigens in GD are the TSHR, the thyroid Tg, which are also thyroid antigens, may be a mechanism for
peroxidase (TPO) enzyme, and Tg. More than 95% of patients disease perpetuation. TSHR autoantibodies can also be “blocking”
14
with GD have detectable circulating TSHR autoantibodies, in nature and prevent receptor activation. This can result in
which are necessary for hyperthyroidism, and approximately 90% hypothyroidism. These two types of autoantibodies can also
15
have detectable TPO autoantibodies. Antibodies directed against coexist, resulting in fluctuating thyroid function. Thus although it
the sodium iodide symporter and the apical iodide transporter, is common to equate GD with hyperthyroidism, individuals with
pendrin, have been reported in smaller numbers of patients. 15 GD may occasionally be hypothyroid or euthyroid (presenting
GD is unique among autoimmune conditions in that with GO).
the TSHR autoantibodies directly stimulate thyroid gland TPO antibodies can be of IgG subclass 1, 2, or 4 and typically
activity. This is exemplified by neonatal GD, where maternal circulate in concentrations 1000fold higher than those of TSHR
TSHR autoantibodies cross the placenta, resulting in transient antibodies. They are directed against two structurally complex
hyperthyroidism in the newborn. However, although TSHR regions of the TPO molecule, the epitopes involving residues
autoantibodies are sufficient to result in transient hyperthyroidism from both the myeloperoxidaselike and the complement control
950 ParT SEvEN Organ-Specific Inflammatory Disease
proteinlike domains. TPO antibodies may have pathogenic CLINICaL PEarLS
significance in that they can fix complement and target the
17
thyrocyte for cellmediated cytotoxicity. In contrast to TSHR Clinical Signs Specific to Graves Disease
antibodies, they do not appear to either stimulate or block the • Graves orbitopathy
enzymatic activity of TPO. • Thyroid bruit
• Thyroid acropachy
Clinical Presentation • Pretibial myxedema
Hyperthyroid GD can present with manifestations affecting
almost any organ system in the body, and as with many endocrine
conditions, affected individuals may report a gradual onset of Investigation and Diagnosis of GD
nonspecific symptoms, typically over a period of months. This The diagnosis of GD is a clinical one, supported by laboratory
often leads to a delay in seeking medical attention and in the investigations. Imaging is occasionally required if the diagnosis
initial diagnosis being made. The signs and symptoms of GD can is in doubt. Thyrotoxicosis is diagnosed biochemically on the
be divided into those associated with hyperthyroidism in general basis of an elevated serum free T 3 (fT 3 ) or free T 4 (fT 4 ) in the
and those specific to GD. These are summarized in Table 70.1. presence of a completely suppressed TSH. If thyrotoxicosis is
found in a patient with extrathyroidal signs, such as GO or
pretibial myxedema, the diagnosis of hyperthyroid GD is clear
and further investigations are not required. If no extrathyroidal
TABLE 70.1 Common and rarer Clinical signs are present, the presence of serum autoantibodies should
Manifestations of Hyperthyroidism be sought. TSHR antibodies are highly sensitive for GD, and
assays are now available in many laboratories. The TSHbinding
Common rare inhibitory immunoglobulin (TBII) assay is also commonly used,
Neuropsychiatric which is an indirect means of detecting TSHstimulating antibod
Anxiety Chorea ies. TPO antibodies are often measured as a surrogate for thyroid
Fatigue and exhaustion Collapse (periodic paralysis) autoimmunity, as the presence of either TSHR antibodies or
Fine tremor Pseudobulbar palsy TPO antibodies has more than 90% sensitivity for GD.
Restlessness and fidgeting Spasticity Imaging is reserved for individuals in whom the diagnosis is
99
not clear. Radionuclide scanning, for example, Tc or 123 I, is
Gastrointestinal favored over ultrasonography, as the former gives functional
Increased appetite Hepatosplenomegaly information on the activity of the thyroid gland, although Doppler
Loose stools
Increased frequency of defecation flow studies are making ultrasound evaluation of the thyroid
Nausea increasingly informative (Fig. 70.4). In GD, there is diffuse uptake
Weight loss in the thyroid gland on radionuclide scanning.
Cardiorespiratory
Palpitations Congestive cardiac failure
Shortness of breath on exertion
Tachycardia (sinus, atrial fibrillation)
Peripheral vasodilation, flushing
Systolic hypertension
Genitourinary
Menstrual irregularities
Cutaneous
Itch Thyroid acropachy
Heat intolerance Pretibial myxedema
Hair loss Onycholysis
Musculoskeletal
Hyperreflexia
Proximal muscle weakness
Ophthalmic
Lid lag Optic neuropathy
Lid retraction
Exophthalmos and proptosis
Eye dryness
Chemosis
Ophthalmoplegia
Miscellaneous 99
FIG 70.4 Tc pertechnetate radionuclide scan image from an
Thirst individual with Graves disease showing diffuse uptake throughout
Thyroid bruit
the thyroid gland.
CHaPTEr 70 Autoimmune Thyroid Diseases 951
GRAVES OPHTHALMOPATHY
Management of GD
The management of hyperthyroid GD can be divided into three Epidemiology
broad categories: medical management, radioiodine (RAI) treat GO is the most common extrathyroidal manifestation of GD.
ment, and surgery. 18 It is clinically apparent in 25–50% of those presenting with GD,
although almost all patients have radiological changes consistent
Medical Management—Antithyroid Drugs with GO to some degree. The peak age of incidence is in the
The thionamide drugs (carbimazole, its metabolite methima fifth and seventh decades of life. GO precedes thyroid gland
zole, and propylthiouracil) compete with Tg to act as substrates dysfunction in about 20% of patients, arises at the same time
for iodination by TPO. Once iodinated, they are metabolized in 40%, and occurs after diagnosis of thyroid dysfunction in the
peripherally, depleting thyroid iodine stores. When the thyroid remaining 40%. Males, older adults, and smokers are more likely
iodine stores are depleted and the intrathyroidal thionamide to have severe disease. Ninetythree percent of cases of GO occur
concentration is high enough, thyroid hormone synthesis is in those with hyperthyroid GD. However, 3% and 4% of GO
abrogated. Most individuals become euthyroid following 4–8 occurs in hypothyroid and euthyroid patients, respectively. A
weeks of treatment; however, euthyroidism may take longer to proportion of these patients with “euthyroid Graves” will eventu
achieve in those with poor medication compliance or with a ally become hyperthyroid; however, some will remain hypothyroid
history of recent iodide exposure. Following initial treatment, or euthyroid despite the presence of TSHR antibodies.
thionamides may either be administered as a fixed high dose,
with levothyroxine supplementation to prevent hypothyroid Etiology
ism (known as a “block and replace” regimen), or at progres GO shares many etiological factors with GD. Smoking is the major
sively lower doses, titrated to allow adequate thyroid hormone environmental risk factor for GO, with smokers or exsmokers
generation. Following 6–18 months of thionamide treatment, four times more likely to develop GO compared with lifelong
about 50% of patients will remain in remission following ces nonsmokers. The number of cigarettes smoked per day correlates
sation of therapy. There is no improvement in remission rate in with the risk of developing GO, suggesting a “dosedependent”
individuals with GD who are treated for longer than 18 months. effect. RAI therapy is also known to occasionally cause flareups
The mechanism of the thionamideinduced remission in GD of GO. This is thought to be largely related to uncontrolled
remains obscure; however, the lymphocytic infiltrate in the postRAI hypothyroidism. Smokers and those with active GO
GD thyroid is rapidly abolished by thionamide treatment, and seem particularly susceptible to this complication, and therefore
serum TSHR and TPO autoantibodies also decrease during RAI is relatively contraindicated in patients with active GO. 19
treatment, suggesting an immunomodulatory effect. It is telling
that several induced murine models of thyroiditis can be amelio Immunopathogenesis
rated by thionamide treatment, suggesting an immunomodula The molecular mechanism that links thyroid dysfunction with
tory role that is distinct from the antithyroid hormone synthesis GO remains incompletely understood. The TSHR is widely
action. If the patient’s disease relapses following medical treat believed to be the primary autoantigen linking the thyroid and
ment, definitive treatment should be considered, as a second the orbit. Orbital fibroblasts (OFs) have been shown to express
course of thionamide treatment rarely induces prolonged cellsurface TSHR, and these are thought to be functional because
remission. of the observation that TSH stimulation in vitro results in an
increase in intracellular cAMP. Mechanistically, the orbital changes
Definitive Treatment that occur in GO are better understood. TSHR autoantibodies
131
Radioactive iodine (RAI) therapy ( I) and surgical thyroid that bind to the TSHR on OFs (or possibly other OF receptors,
ectomy are both efficacious treatments for GD, effectively such as the insulinlike growth factor receptor; IGF1R) are
removing functional thyroid tissue and rendering the patient believed to activate OFs to secrete cytokines and chemokines,
hypothyroid and dependent on levothyroxine replacement over which attract lymphocytes and other inflammatory cells. These
the long term. RAI therapy takes advantage of the thyroid’s infiltrate the orbital tissues, augmenting further the proinflam
ability to concentrate iodine. RAI is administered orally and matory cytokine environment, causing OFs to proliferate and
20
concentrates in the thyroid, primarily emitting betaradiation to secrete excessive GAGs. GAGs accumulate in the extraocular
to produce local thyrocyte DNA damage. These cells then muscles, increasing their size. These matrix molecules are also
undergo necrotic change, and the thyroid atrophies over the osmotically active, resulting in edema and swelling of surrounding
subsequent year. RAI renders more than 80% of those with GD tissues. In addition, the adaptive arm of the immune system is
hypothyroid and needing longterm thyroid hormone replace thought to interact via HLA and CD40 molecules expressed by
ment. RAI is generally well tolerated, and longterm followup the OFs to increase the presentation of autoantigens, thus
studies in adults have shown reassuring results with regard to perpetuating the cycle. OFs are also thought to differentiate into
carcinogenicity. RAI is absolutely contraindicated in pregnancy adipocytes, resulting in increased retroorbital fat deposition. The
and is best avoided in those with active, inflammatory GO. Total resulting inflammation gives rise to redness and edema of the
or neartotal thyroidectomy is also an effective treatment for orbital tissues, with the cellular proliferation and GAG accumula
GD and is particularly suitable for individuals with a large tion producing proptosis (protrusion of the eyeball from the
goiter, those with severe hyperthyroidism who cannot tolerate socket), increased intraorbital pressure, and restriction of
thionamides, or in those with active GO when RAI is relatively extraocular eye movements. 20
contraindicated. The complications of thyroidectomy include
change in voice because of intraoperative damage to the recur Diagnosis and Clinical Presentation
rent laryngeal nerve and hypocalcemia (often transient) caused When the clinical signs of GO are associated with thyroid dysfunc
by parathyroid gland damage. tion and/or circulating thyroid autoantibodies, the diagnosis is
952 ParT SEvEN Organ-Specific Inflammatory Disease
A B
FIG 70.5 (A) Clinical photograph of the eyes of an individual with Graves ophthalmopathy prior
to treatment. (B) Clinical photograph of the same patient’s eyes following surgical orbital decom-
pression and rehabilitative surgery.
Amenable to surgical rehabilitation TABLE 70.2 assessment of Graves
Ophthalmopathy (GO)
a: The “NO SPECS” Classification System to assess the
Severity of GO
Severity/Activity Class 0—No signs or symptoms
Class 1—Only signs (limited to upper lid retraction and stare, with or
without lid lag)
conjunctival injection, etc.)
Disease severity Class 2—Soft tissue involvement (edema of conjunctivae and lids,
Class 3—Proptosis
Class 4—Extraocular muscle involvement (usually with diplopia)
Disease activity
Class 5—Corneal involvement (primarily due to lagophthalmos, the
inability to completely close the eyelids)
Amenable to medical therapy Class 6—Sight loss (caused by optic nerve involvement)
Time
FIG 70.6 Rundle curve illustrating the natural history of Graves B: The Clinical activity Score (CaS) to assess activity
ophthalmopathy. of GO
A single point is scored for each of the features present. Each feature
has equal weighting. A higher score indicates more active disease.
generally straightforward. If proptosis is completely unilateral, 1. Spontaneous orbital pain
or GO features occur without upper lid retraction, then the 2. Gaze evoked orbital pain
3. Eyelid swelling that is attributed to active GO
diagnosis needs to be confirmed by imaging, as the differential 4. Eyelid erythema
diagnosis for unilateral proptosis is a spaceoccupying retroorbital 5. Conjunctival redness that is considered to be due to active GO
lesion. The patient with GO may complain of gritty, watery, or 6. Chemosis
uncomfortable eyes, with or without a change in appearance 7. Inflammation of caruncle or plica
(upper eyelid retraction, soft tissue swelling, redness of the eyes, 8. Increase of >2 mm in proptosis
and proptosis) (Fig. 70.5). Diplopia occurs if eye movements 9. Decrease of >8 degrees in uniocular ocular excursion in any one
direction
are restricted by stiffness of the extraocular muscles or high 10. Decrease of acuity equivalent to 1 Snellen line
intraorbital pressure. Deteriorating visual acuity and color
desaturation are sinister symptoms in GO, indicating incipient
optic neuropathy.
GO has a predictable and generally monophasic natural history support. The general health benefits of smoking cessation are
(Fig. 70.6). There is an early phase of increasing disease activity numerous; in addition, smokers are more likely to relapse after
that can be targeted by medical therapy, and it is followed by a a course of medical therapy compared with nonsmokers.
plateau phase and then gradual improvement until a stable, In parallel to restoring and maintaining euthyroidism, the
inactive phase is reached. GO manifestations can be classified successful treatment of GO depends on staging the activity and
in two ways: on the basis of severity, which indicates the extent severity of the disease. In patients with mild, active GO, an
of functional, anatomical, and cosmetic features; and on the observational policy can be employed with symptomatic measures,
basis of activity, which denotes the intensity of any acute inflam such as artificial tears and dark glasses. Selenium supplements,
matory reaction. Severity of GO is assessed using the “NO SPECS” at a dose of 100 µg twice daily for 6 months, have been shown
classification system (Table 70.2, panel A) and activity is assessed to significantly improve quality of life, slow disease progression,
21
using the clinical activity score (CAS) (see Table 70.2, panel B). and reduce ocular involvement in these patients. In those with
19
A CAS of 3 or more indicates active GO. These classifications moderate to severe, active, and progressive GO, a course of oral
allow determination of which patients require treatment and or intravenous (IV) glucocorticoids (steroids) is indicated. Orbital
which therapy is most appropriate. radiotherapy is also efficacious in people with active inflammation
and diplopia, but since it has a delayed onset of action, it often
Treatment needs to be used in conjunction with other therapies, such as
Patients with GD (with and without GO) should be strongly steroids or orbital decompression surgery. In patients with sight
encouraged to stop smoking and offered smoking cessation threatening optic neuropathy, highdose IV steroids are used,
CHaPTEr 70 Autoimmune Thyroid Diseases 953
and orbital pressure is relieved by urgent orbital decompression effect. These data highlight the need to further investigate the
surgery. In patients whose eyelids do not close completely, eye MHC region to clarify its role in AH susceptibility.
ointments and protective eye pads are essential to protect the In common with GD, the CTLA-4 gene also appears to influ
eyes against corneal damage and ulceration. Once disease activity ence AH susceptibility. Three CTLA-4 polymorphisms have been
has burned out, rehabilitative surgery can greatly improve the associated with AH in a number of populations. An A/G SNP
function and cosmetic appearance of the eyes. Orbital decompres located downstream of the 3’UTR (designated CT60), an A/G
sion, strabismus correction, and eyelid surgery are commonly polymorphism at codon 17, and a 106bp microsatellite repeat
used procedures. 22 in the 3’UTR of exon 3. A locus on chromosome 8q24 containing
the thyroglobulin gene was linked to AH, and a number of SNPs
FUTURE DEVELOPMENTS FOR GRAVES were subsequently studied in AH individuals with modest reported
HYPERTHYROIDISM AND OPHTHALMOPATHY ORs for association of between 1.32 and 1.56. Other loci impli
cated in AH susceptibility include the tumor necrosis factor
Novel approaches to modulating the immune response in GD (TNF-α) gene, PTPN22, CYP27B1, Tcell receptor (TCR) genes,
and GO as a therapeutic strategy are under investigation. In light and several immunoglobulin genes and cytokine regulatory genes.
of the significant side effects associated with steroid therapy In contrast to GD, environmental factors in AH susceptibility
for GO, steroidsparing agents, including methotrexate and have been challenging to identify. However, the role of iodine is
mycophenolate mofetil, are of particular interest. Novel biological widely accepted, since population studies have reported an increase
agents have been evaluated to a limited extent in these condi in the prevalence of thyroid lymphocytic infiltration and auto
23
tions and are subject to further ongoing studies. Rituximab, antibodies following public health salt iodization programs.
a CD20 monoclonal antibody (mAb) that depletes circulating Infectious agents have also been implicated in susceptibility to
B cells, appeared to be potentially efficacious in early studies; AH. Several studies have identified an increased prevalence of
however, in two randomized controlled trials in individuals with IgG and/or IgA antibodies to virulenceassociated outer mem
moderate to severe active GO, results have been conflicting, and brane proteins of Yersinia enterocolitica in AH patients and in
therefore further studies are now needed. A longerterm goal is relatives of individuals with AH, suggesting that susceptibility
the development of an anti–TSHR antibody or small molecule genes for Yersinia infection may also confer risk for AH.
antagonist that could block binding of stimulatory TSHR anti The effect of radiation, either “internal” (nuclear “fallout” or
bodies or inhibit TSHR signaling, thus ameliorating the cause of from RAI treatment) or “external” (radiotherapy or direct
hyperthyroidism. exposure during a nuclear accident), on AH susceptibility has
been extensively studied. Following the nuclear reactor accident
AUTOIMMUNE HYPOTHYROIDISM at Chernobyl, a rise in thyroid autoantibodies was noted 15 years
following exposure; however, this was not accompanied by thyroid
25
The most common cause of autoimmune hypothyroidism (AH) dysfunction. Longterm followup studies of thyroid function
is chronic (or lymphocytic) autoimmune thyroiditis. There are in Japanese survivors of the atomic bombing of Nagasaki and
two variants, atrophic and goitrous (Hashimoto thyroiditis). Hiroshima have demonstrated a clear link between radiation
exposure and thyroid cancer; however, the association with AH
Epidemiology remains disputed. One study, at 40 years followup, demonstrated
In populations living in iodine sufficient areas, AH is common, a significant relationship between dose of radiation exposure at
affecting between 1 and 10% of the population. The prevalence Nagasaki and AH. However, a further study, at more than 50
increases with age, with 3–20% of individuals over 75 years of years of followup, showed that radiation exposure did not
age being hypothyroid. Like GD, AH is more common in women correlate with either the occurrence of thyroid autoantibodies
than in men. In a UK community survey, the incidence of or AH. 26
hypothyroidism in women was 3.5/1000/year, which increased
to 13.7/1000/year in women between 75 and 80 years of age. In Immunopathogenesis
men, the incidence was just 0.6/1000/year. 24 The mechanisms by which tolerance to thyroid antigens is
lost in the first instance remain obscure. It appears that both
Etiology a susceptible genetic background and a permissive environ
AH, like GD, is a complex genetic condition. Familial clustering ment are required before AH develops. Notably, AH is much
provides evidence for a genetic etiology, which, in several studies, more frequent in the autoimmune polyendocrinopathy type 1
appears stronger than that for GD. The λs for AH is estimated (APECED) syndrome than GD, suggesting that central thymic
to be between 10 and 45, suggesting that AH is more heritable Tcell selection, and therefore central tolerance, may be more
compared with GD. In families with autoimmunity, frequently important in AH than in GD. Histologically, lymphocytic
a mixture of individuals affected by AH and GD are seen, sug infiltrates can be seen in the thyroid, consisting of both T and
gesting some shared genetic factors. The differing prevalence of B cells (Fig. 70.7). These infiltrates can be diffuse or focal.
AH in different ethnic groups, with AH being more common Scarring and fibrosis may also be seen, with destruction of the
in Caucasian than in black populations, also supports a genetic normal thyroid architecture and an absence of colloid in thyroid
background. Knowledge about the genetics of AH is limited. follicles.
The MHC class II HLA-DR3, DR4, and DR5 alleles have Both cellmediated and humoral immune mechanisms are
been associated with AH in Caucasians only. Conflicting results important in the continuing thyroid damage seen in AH. T cells
have been reported for HLA-DQ alleles. One study reported that are known to play a pivotal role in both the initiation and perpetu
the HLA-DQ alleles DQA1*0301 and DQB1*0201 confer sus ation of AH. Studies in which researchers induced hypothyroidism
ceptibility to AH in Caucasians, with certain HLA-DQ alleles in Rag1deficient transgenic mice that were unable to produce
27
(DQA1*0102 and DQB1*0602) reported to confer a protective autoantibodies confirm this. T cells respond to antigenpresenting
954 ParT SEvEN Organ-Specific Inflammatory Disease
TABLE 70.3 Common and rare Clinical
Manifestations of Hypothyroidism
Common rare
Neuropsychiatric
Lethargy Cerebellar ataxia
Impaired cognitive function Deafness
Slow speech Psychosis
Depression
Gastrointestinal
Anorexia Ascites
Weight gain
Constipation and bloating
Abnormal liver function tests
FIG 70.7 Lymphocytic infiltration of the thyroid in a patient with Cardiorespiratory
autoimmune hypothyroidism. Shortness of breath on exertion Pericardial effusion
Reduced exercise tolerance
Bradycardia
Diastolic hypertension
Cardiomegaly
cells (APCs) and release cytotoxic and lytic factors, which result Low-voltage electrocardiogram
in thyrocyte death. Thyroid follicular cells have themselves been Peripheral edema (nonpitting)
demonstrated to express HLA class II molecules, suggesting that
they may also have a direct role in antigen presentation. Genitourinary
The humoral immune response is also important in AH. More Oligomenorrhea, amenorrhea, menorrhagia
than 90% of individuals with AH have detectable TPO antibodies. Reduced libido
Autoantibodies directed against Tg and, to a lesser degree, the Early fetal loss
TSHR are also commonly detected. In vitro, TPO antibodies Impotence
17
can fix complement and directly induce cell damage. Their
presence within thyroid follicles in AH patients suggests they Cutaneous
may have the same effect in vivo, although the thyrocyte destruc Cold intolerance
Skin dryness and thickening
tion found in the Rag1-deficient mouse suggests TPO antibodies Malar flush
are not necessary for AH. Interestingly, the epitopes toward which Edema of the face, hands, and feet
TPO antibodies are directed in both GD and AH overlap, and Change in face shape
17
there is no disease specificity for the targeted TPO domain. Pallor
TSHR autoantibodies found in rare patients with AH are likely Nail abnormalities
to exert a blocking or antagonist effect, thus inducing hypothyroid Alopecia
ism. As thyroid hormone secretion falls, increasing thyrocyte Musculoskeletal
stimulation by elevation of serum TSH may induce or augment
thyroid autoantigen expression (e.g., TPO, Tg), thereby perpetuat Bradykinesia
Joint and muscular pains
ing the autoimmune response. Delayed relaxation of tendon reflexes
Clinical Presentation Miscellaneous
Hypothyroidism can result in changes in almost every organ Goiter (in Hashimoto thyroiditis)
system in the body (Table 70.3). Initially, the signs and symptoms Reduced basal metabolic rate
may be subtle and nonspecific, including tiredness, cold sensitivity, Increased sensitivity to exogenous insulin
and constipation. Hypothyroidism is frequently diagnosed Abnormal lipid metabolism
incidentally following blood tests for another problem. The typical
goiter palpable in Hashimoto thyroiditis is moderate in size and
firm with a finely granular surface. Individuals often report a but this investigation is generally only indicated if a discrete
gradual increase in size over a number of years. However, rapid nodule is present.
growth is unusual. In atrophic AH, the size of the thyroid gland Reflecting the effects of hypothyroidism on multiple organ
is reduced. systems, many biochemical and hematological abnormalities,
such as mild anemia, hyponatremia, or elevated serum creatine
Investigation and Diagnosis kinase, transaminases, lactate dehydrogenase, and lowdensity
Hypothyroidism is detected biochemically by a raised serum lipoprotein (LDL) cholesterol, are also commonly detected in
TSH with reduced fT 4 . AH is differentiated from other forms of patients with AH.
hypothyroidism by the presence of circulating autoantibodies,
including TPO and Tg. On ultrasound scanning, the thyroid Management
gland appears finely heterogeneous and hypoechoic, a change AH requires lifelong treatment with thyroid hormone replacement
that predates serum autoantibody positivity in some. Fineneedle therapy. The most commonly prescribed is synthetic thyroxine,
aspiration (FNA) demonstrates lymphocytes and Hürthle cells, levothyroxine (LT 4 ), which is widely available and inexpensive.
CHaPTEr 70 Autoimmune Thyroid Diseases 955
Except for individuals with known heart disease or the very old, 1–4 months. During the thyrotoxic phase, preformed thyroid
a full, weightrelated replacement dose (≈1.6 µg/kg/day) should hormone stores are released from the thyroid follicles, leading
be started. Once the patient is on a stable dose, thyroid function to thyrotoxicosis, which may be severe. The hypothyroid phase
should be assessed annually to ensure that the patient continues follows when these preformed stores are exhausted and the thyroid
to receive the appropriate dose. Some commonly prescribed has become depleted of hormones. In about 90% of cases this
medications, such as calcium and iron supplements, and proton hypothyroidism is transient, but in some cases, it never resolves.
pump inhibitors interfere with the absorption of LT 4 , and patients
should be advised to take these at least 4 hours before or after POSTPARTUM THYROIDITIS
their LT 4 to ensure maximum absorption.
Postpartum thyroiditis (PPT) is a common endocrine condition
Subclinical Hypothyroidism that manifests within 1 year following pregnancy. It affects
29
Although the need to treat individuals with overt AH is universally between 5% and 10% of women in the general population. PPT
accepted, it is unclear whether thyroid hormone replacement is is classically a biphasic disorder, consisting of a period of transient
beneficial in individuals with persistent subclinical hypothyroidism thyrotoxicosis (median onset 12–14 weeks post partum) followed
(serum TSH raised, but fT 4 and fT 3 within the normal reference by a period of transient hypothyroidism (median onset 18–20
range on at least two separate occasions). Progression to overt weeks post partum); however, a monophasic (thyrotoxicosis or
hypothyroidism from this state occurs in about 2% of individuals hypothyroidism alone) or reversed biphasic (hypothyroidism
per year who are TPO antibody negative, rising to 5% per year followed by thyrotoxicosis) pattern can also occur. During
if antibodies are present. Persistent subclinical hypothyroidism pregnancy, there is a state of relative immune tolerance, followed
has been associated with a number of markers of cardiac and by a rebound in immune function following delivery, coinciding
vascular dysfunction in observational studies, including left with the occurrence of PPT. The presence of thyroid autoantibod
ventricular diastolic dysfunction, increased vascular resistance, ies and a lymphocytic infiltrate on thyroid biopsy supports an
and atherosclerosis. A randomized controlled study is now autoimmune basis for this condition. 29
underway to determine whether thyroid hormone replacement Clinically, the thyrotoxic phase of PPT is often mild, resulting
can be used to improve cardiovascular outcomes in patients with in symptoms of fatigue and irritability, which can be misdiagnosed
persistent subclinical hypothyroidism. 28 as postnatal depression. If the thyrotoxic episode is short, it may
even go unnoticed. Neck pain is not a feature. Women with
CLINICaL PEarLS PPT who are thyrotoxic may benefit from a betablocker, such
as propranolol, for symptom relief. Antithyroid drugs are not
Management of Persistent Subclinical effective, as the thyrotoxicosis is caused by release of preformed
Hypothyroidism thyroid hormones. Following the episode of thyroid dysfunction,
29
10–20% of women remain permanently hypothyroid. In women
• If thyroid-stimulating hormone (TSH) is elevated, immediate treatment who have had PPT and then recovered, an annual assessment
should be offered: of thyroid function is recommended, as their risk of longterm
• In pregnancy 29
• Preconception, if planning a pregnancy hypothyroidism is considerable. In those women who return
• If TSH is elevated but <10 mIU/L, a trial of treatment can be offered: to being euthyroid, there is a 75% risk of PPT in subsequent
• To individuals with convincing symptoms of hypothyroidism pregnancies and a 50% risk of permanent hypothyroidism at
• If TSH is >10 mIU/L, treatment should be offered: 7 years. 30
• To individuals under the age of 70 years
• To individuals over the age of 70 years if there is a clear history of
hypothyroid symptoms or there are significant risk factors for TRANSLATIONAL RESEARCH
cardiovascular disease.
ON THE HOrIZON
FUTURE DEVELOPMENTS New Approaches to Therapy of Graves Disease
The genetics of AH remain understudied considering its frequency • Novel immunotherapeutic agents for Graves orbitopathy
as the commonest autoimmune disease in humans. Considerable • Anti–thyroid-stimulating hormone receptor (TSH-R) blocking antibodies
for control of hyperthyroid Graves disease
work remains to be done on whether treatment of subclinical • Small molecule TSH receptor antagonists for management of hyper-
hypothyroidism is beneficial. Given the insidious nature of the thyroidism in Graves disease
development of AH, it remains a good target for a preventative
immunotherapeutic intervention, if a safe and economic treatment
can be found. The major challenge of the next 5–10 years is to take novel
immunotherapeutic agents, including “biologicals” that have
OTHER FORMS OF THYROIDITIS been developed for rheumatic disorders into the clinical arena
for autoimmune thyroid diseases. The primary target of these
The term thyroiditis relates to conditions resulting in inflammation efforts should be GO, which remains a disfiguring condition,
of the thyroid gland. A number of etiologies have been described, often with substantial functional impairment of vision and
including infection, radiation exposure, drugs, and autoimmune associated low quality of life. Two randomized controlled trials
factors. A common pattern to the natural history of several of Blymphocyte–depleting agents have yielded conflicting results,
thyroiditides is frequently seen, involving an initial thyrotoxic and therefore other powerful agents need to be investigated as
phase of 1–3 months, followed by a rapid drop in serum thyroid this remains a disorder with no wholly satisfactory treatment.
hormones and a transient hypothyroid phase, often lasting another Early diagnosis of GO and development of markers that predict
956 ParT SEvEN Organ-Specific Inflammatory Disease
progressive or severe disease will also be helpful in identifying reconstitution in patients with advanced human immunodeficiency virus
patients for early intervention. The development of anti–TSHR– (HIV) disease. Medicine (Baltimore) 2005;84:98–106.
blocking antibodies as a therapeutic agent for hyperthyroid GD 14. Smith BR, Bolton J, Young S, et al. A new assay for thyrotropin receptor
seems likely. These agents might have a role in patients unlikely autoantibodies. Thyroid 2004;14:830–5.
to gain medical remission from thionamide antithyroid drugs 15. Czarnocka B. Thyroperoxidase, thyroglobulin, Na(+)/I(−) symporter,
pendrin in thyroid autoimmunity. Front Biosci 2011;16:783–802.
or in those for whom rapid control of hyperthyroidism is desir 16. Costagliola S, Bonomi M, Morgenthaler NG, et al. Delineation of the
able. Smallmolecule TSHR antagonists may also come to the discontinuousconformational epitope of a monoclonal antibody
clinic, with a similar role. displaying full in vitro and in vivo thyrotropin activity. Mol Endocrinol
2004;18:3020–34.
Please check your eBook at https://expertconsult.inkling.com/ 17. McLachlan SM, Rapoport B. Thyroid peroxidase as an autoantigen.
for selfassessment questions. See inside cover for registration Thyroid 2007;17:939–48.
details. 18. Hegedus L. Treatment of Graves’ hyperthyroidism: evidencebased and
emerging modalities. Endocrinol Metab Clin North Am 2009;38:355–71,
ix.
REFERENCES 19. Perros P, Dayan CM, Dickinson AJ, et al. Management of patients with
Graves’ orbitopathy: initial assessment, management outside specialised
1. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease
in a community: the Whickham survey. Clin Endocrinol (Oxf) centres and referral pathways. Clin Med (Lond) 2015;15:173–8.
1977;7:481–93. 20. Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010;362:726–38.
2. Laurberg P, Pedersen KM, Vestergaard H, et al. High incidence of 21. Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of
multinodular toxic goitre in the elderly population in a low iodine intake mild Graves’ orbitopathy. NEJM 2011;364:1920–31.
area vs. high incidence of Graves’ disease in the young in a high iodine 22. Bartalena L, Baldeschi L, Dickinson A, et al. Consensus statement of the
intake area: comparative surveys of thyrotoxicosis epidemiology in European Group on Graves’ orbitopathy (EUGOGO) on management of
EastJutland Denmark and Iceland. J Intern Med 1991;229:415–20. GO. Eur J Endocrinol 2008;158:273–85.
3. Brix TH, Kyvik KO, Christensen K, et al. Evidence for a major role of 23. Salvi M, Campi I. Medical treatment of Graves’ orbitopathy. Horm Metab
heredity in Graves’ disease: a populationbased study of two Danish twin Res 2015;47:779–88.
cohorts. J Clin Endocrinol Metab 2001;86:930–4. 24. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of
4. Vaidya B, KendallTaylor P, Pearce SH. The genetics of autoimmune thyroid disorders in the community: a twentyyear followup of the
thyroid disease. J Clin Endocrinol Metab 2002;87:5385–97. Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55–68.
5. Eschler DC, Hasham A, Tomer Y. Cutting edge: the etiology of 25. Agate L, Mariotti S, Elisei R, et al. Thyroid autoantibodies and thyroid
autoimmune thyroid diseases. Clin Rev Allergy Immunol 2011;41:190–7. function in subjects exposed to Chernobyl fallout during childhood:
6. Ueda H, Howson JM, Esposito L, et al. Association of the Tcell evidence for a transient radiationinduced elevation of serum thyroid
regulatory gene CTLA4 with susceptibility to autoimmune disease. antibodies without an increase in thyroid autoimmune disease. J Clin
Nature 2003;423(6939):506–11. Endocrinol Metab 2008;93:2729–36.
7. Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele 26. Imaizumi M, Usa T, Tominaga T, et al. Radiation doseresponse
of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant relationships for thyroid nodules and autoimmune thyroid diseases in
of Graves’ disease. J Clin Endocrinol Metab 2004;89:5862–5. Hiroshima and Nagasaki atomic bomb survivors 5558 years after
8. Brent GA. Environmental exposures and autoimmune thyroid disease. radiation exposure. JAMA 2006;295:1011–22.
Thyroid 2010;20:755–61. 27. Quaratino S, Badami E, Pang YY, et al. Degenerate selfreactive human
9. Vestergaard P. Smoking and thyroid disorders—a metaanalysis. Tcell receptor causes spontaneous autoimmune disease in mice. Nat Med
Eur J Endocrinol 2002;146:153–61. 2004;10:920–6.
10. Cawood TJ, Moriarty P, O’Farrelly C, et al. Smoking and 28. Pearce SHS, Brabant G, Duntas LH, et al. 2013 ETA guideline:
thyroidassociated ophthalmopathy: a novel explanation of the biological management of subclinical hypothyroidism. Eur Thyroid J 2013;2:215–28.
link. J Clin Endocrinol Metab 2007;92:59–64. 29. LandekSalgado MA, Gutenberg A, Lupi I, et al. Pregnancy, postpartum
11. Winsa B, Adami HO, Bergström R, et al. Stressful life events and Graves’ autoimmune thyroiditis, and autoimmune hypophysitis: intimate
disease. Lancet 1991;338:1475–9. relationships. Autoimmun Rev 2010;9:153–7.
12. MatosSantos A, Nobre EL, Costa JG, et al. Relationship between the 30. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid
number and impact of stressful life events and the onset of Graves’ dysfunction during pregnancy and postpartum: an Endocrine Society
disease and toxic nodular goitre. Clin Endocrinol (Oxf) 2001;55:15–19. clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543–65.
13. Chen F, Day SL, Metcalfe RA, et al. Characteristics of autoimmune 31. Davies TF, Ando T, Lin RY, et al. Thyrotropin receptorassociated diseases:
thyroid disease occurring as a late complication of immune from adenomata to Graves’ disease. J Clin Invest 2005;115:1972–83.
CHaPTEr 70 Autoimmune Thyroid Diseases 956.e1
MULTIPLE-CHOICE QUESTIONS
1. When assessing an individual with thyrotoxicosis, which feature A. Proptosis of the eyes
is NOT consistent with a diagnosis of Graves disease? B. Pretibial myxedema
A. Increasing severity of symptoms over weeks to C. Previous history of Graves disease
months D. Goiter with a bruit
B. Grittiness of the eyes and blurred vision on waking in the E. Onset of symptoms 4 months after delivery
morning 3. In moderate to severe Graves ophthalmopathy (GO), the
C. Neck pain following treatments are evidence based and effective except:
D. A family history of autoimmune hypothyroidism and A. Oral selenium supplements
pernicious anemia B. Topical lubricants
E. Relief of symptoms with betablocker medication
C. Systemic glucocorticoids
2. Which of the listed clinical features is in keeping with a D. Orbital radiotherapy
diagnosis of postpartum thyroiditis (PPT)? E. Orbital decompression surgery
71
Type 1 Diabetes
Leonard C. Harrison
Diabetes is not a single disease but a metabolic syndrome in be diagnosed clinically. However, in Caucasians, the diagnosis
which different mechanisms lead to deficiency of insulin and/ can be confirmed and in older individuals and less clear-cut cases
or impaired insulin action and persistent hyperglycemia. The may be clearly established by detecting circulating autoantibodies
American Diabetes Association classified diabetes into four cat- to islet antigens. These autoantibodies to insulin (IAAs), glutamic
egories based on etiology rather than age of onset (juvenile-onset acid decarboxylase 65 000 mol. wt. isoform (GADA), insulinoma-
versus adult-onset) or requirement for insulin therapy (insulin- like antigen-2 (IA-2A), and zinc transporter-8 (ZTA) are markers
1
dependent versus noninsulin-dependent). The vast majority of of β-cell autoimmunity that appear many months to years before
2-5
cases, approximately 10% and 90%, respectively, are attributed to symptoms and therefore denote high risk for clinical disease.
type 1 and type 2 diabetes. This chapter focuses mainly on type They are present in at least 90% of Caucasian children with
1 diabetes, which results from an absolute deficiency of insulin T1DA (compared with ≈1% of the background population)
secondary to the loss of pancreatic β cells. Type 1 diabetes is but in only ≈50% of Hispanic American and African American
classified as 1A (immune-mediated) or 1B (idiopathic), primarily children, an increasing number of whom have T2D and, in some
depending on the presence or absence, respectively, of pancreatic cases, T1DB. Negative results for islet autoantibodies in children
islet autoantibodies. However, as discussed below, type 1A diabetes with diabetes should also alert to the possibility of monogenic
(T1DA) and type 1B diabetes (T1DB) also differ in their natural maturity-onset diabetes of the young (MODY) and sulfonylurea
history and clinical features. receptor syndromes.
1
Diabetes is diagnosed on the basis of the following criteria : The hallmark of T1DA is progression to absolute insulin
symptoms in association with a casual plasma glucose ≥200 mg/dL deficiency within several years after diagnosis. The connecting
(11.1 mmol/L) OR fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) peptide in proinsulin (C-peptide) is secreted in an equimolar
OR 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) in an oral ratio to insulin and is used as a surrogate for insulin to evalu-
glucose tolerance test (OGTT; 75 g glucose in water). Without ate residual β-cell function in the face of exogenous insulin or
symptoms, the diagnosis of diabetes must rest on confirmation IAAs, or insulin antibodies induced by exogenous insulin. The
of a raised plasma glucose concentration. A further diagnostic plasma C-peptide in response to a mixed meal tolerance test is
criterion introduced by the World Health Organization (WHO) the gold standard. Although children with T1DA have lost most
in 2011, in particular for the diagnosis of type 2 diabetes, is a of their β-cell function at diagnosis, the measurement of plasma
confirmed blood glycated hemoglobin (HbA 1c ) ≥48 mmol/mol C-peptide is not a reliable way of distinguishing T1D, especially
(6.5%). Because HbA 1c is an integrated measure of glycemia over at diagnosis. Hyperglycemia impairs β-cell function, and when
many weeks, it is not suitable for diagnosing children or in the corrected by rehydration and insulin replacement, it may be
following circumstances: suspected type 1 diabetes; symptoms of followed by a “honeymoon phase” of partial recovery of β-cell
diabetes for <2 months; acute illness; medication that may increase function and a decreased requirement for exogenous insulin that
blood glucose (e.g., steroids, antipsychotics); and pregnancy. The may last many months. By several years after diagnosis, most
criteria for diagnosing gestational diabetes are stricter: fasting young children display little residual β-cell function; however,
plasma glucose ≥101 mg/dL (5.6 mmol/L) or 2-hour plasma in older children and adults, residual C-peptide secretion has
glucose in an OGTT ≥140 mg/dL (7.8 mmol/L). been observed for many years and is believed to be associated
The classic symptoms and signs of T1DA, because of high with better glycemic control.
concentrations of blood glucose, are polyuria, polydipsia, and Classically, T1DA was considered a disease of “juvenile onset”
unexplained weight loss; others include fatigue, increased hunger, in normal-weight individuals in contrast to type 2 diabetes with
impaired visual acuity as a result of changes in the refractive index onset in middle-aged, overweight individuals. However, this view
6
of vitreous humor, tingling or numbness in the hands or feet requires reappraisal. First, 5–10% of adults who present with
resulting from sensory nerve changes, and vaginal irritation caused diabetes diagnosed initially as T2D and are typically overweight,
by Candida infection. If diabetes is undiagnosed or untreated, have evidence of low-grade islet autoimmunity manifest by the
7
failure to metabolize glucose will result in the breakdown of fat, presence of GADAb, and occasionally IA-2Ab or ZTAb. If we
leading to ketonemia and ketoacidosis, which may be accompanied accept that they have a slowly progressive form of autoimmune
by nausea and hyperventilation before life-threatening ketoacidotic β-cell destruction, that was termed latent autoimmune diabetes
coma. In children presenting with the classic symptoms, T1D can in adults (LADA), their number doubles the prevalence of T1DA.
957
958 Part seven Organ-Specific Inflammatory Disease
Second, the “obesity epidemic” has impacted on the T1D and the population distribution of specific-risk HLA genes, which
T2D stereotypes. “Hybrid” types with β-cell autoimmunity and account for up to 50% of the lifetime risk for T1DA. However,
insulin resistance (“double diabetes”) are becoming increasingly the incidence of T1DA is rising in many countries on a back-
common, characterized by weaker immune and genetic markers ground of lower-risk HLA alleles. In Western societies, the
(lower avidity autoantibodies predominantly to GAD and lower incidence in childhood has more than doubled since the 1980s
risk human leukocyte antigen [HLA] alleles). Low-grade innate and has been rising at ≈3% annually, particularly among younger
12
immune inflammation, associated with insulin resistance in children. The same trend is also occurring in other countries,
obesity, could promote and uncover latent β-cell autoimmunity such as Kuwait and Saudi Arabia, and some parts of India and
in individuals with lower-risk genes for T1DA. China, where Western lifestyles have been adopted but where
T1DB excludes known specific causes of β-cell dysfunction, the prevalence of high-risk HLA genotypes for T1DA is much
such as monogenic diabetes. It encompasses forms of ketosis- lower. Just as in T2D, environmental factors may increase the
prone diabetes initially described in West Africans and African penetrance of risk genes for T1DA. In the case of HLA genes in
8
Americans and subsequently in other ethnic groups, but rarely Caucasians, the increasing incidence of T1DA is accounted for
seen in Caucasians. Obesity and relatively well-preserved residual by children with intermediate-risk (DR 4,4 or DR 3,3) or low-risk
β-cell function were features of the African cases. T1DB also (DR 4,X or DR 3,X) phenotypes, not the highest-risk HLA
13
includes fulminant diabetes initially described in Japan, where phenotypes (DR 3,4; DQ 2,8). These lower-risk phenotypes
it may account for 15–20% of new-onset T1D, and subsequently are also the ones seen in non-Caucasians and adults with T1DA.
elsewhere in Asia. 9,10 Fulminant diabetes is associated with The greatest number of children with diabetes will soon be found
widespread mononuclear cell infiltration of both the exocrine in the most populous regions of the world, that is, India and
and endocrine pancreas, and elevated concentrations of serum China. The impact of the modern Western environment on T1DA
pancreatic amylase, elastase, and lipase, in individuals with HLA is discussed further below.
10
susceptibility genes for T1D. Case reports have associated it T1DA affects both sexes equally in childhood, with a slight
with acute viral infection and drug hypersensitivity reactions, excess of males in early adult life. Of newly diagnosed cases, no
but its etiology remains unclear. In Caucasians, T1DB includes more than 10–15% have a family history of T1DA. However,
T1D, in which islet autoantibodies are undetectable, but the studies of affected families have provided major insights into
latter may reflect assay insensitivity on a particular occasion. A the genetics and natural history of T1DA. In relatives with T1DA,
classification of diabetes that hinges on the presence or absence the rate of progression to clinical diabetes is positively associated
of islet autoantibodies is clearly not ideal. β cell–specific T cells, with the number and titer of islet autoantibodies, 2,3,5 the number
not islet autoantibodies, are the effectors of β-cell damage, and of HLA class 2 risk alleles (DR3, DR4) and specific HLA class I
14
15
reciprocal relationships between autoantibodies and autoreactive alleles (A24), and the degree of insulin resistance and is
11
T cells to islet antigens have been reported. In addition, the negatively correlated with age. The specificity of autoantibodies
more recent discovery of autoantibodies to ZT8 suggests the is also important. IAAs are more often the first sign of islet
possibility that autoantibodies to islet antigens remain to be autoimmunity in children who are followed up from birth and,
2-5
discovered and might be markers of particular subtypes of T1D. of all the autoantibodies, has the highest predictive value. In
For example, in fulminant diabetes, the clinical picture suggests Europe, North America, and Australia, birth cohort studies of
that if autoimmunity is involved, it targets the exocrine pancreas. children who have a relative with T1DA have shown that the
Furthermore, in contrast to T1DA, in which there is an extended development of diabetes by the age of 18 years is almost always
preclinical history of islet autoimmunity, autoantibodies may associated with the appearance of islet autoantibodies in the
5
not be present at the time when fulminant diabetes presents first few years of life. Of children with ≥2 islet autoantibodies
acutely. before the age of 3 years, 57% (95% confidence interval [CI]
51.7–62.3%) and 74.8% (95% CI 69.7–79.9%) progressed to
CLInICaL PearLs diabetes by 6 and 10 years of age, respectively. With a single islet
autoantibody, 14.5% progressed to diabetes by 10 years of age.
• The type 1 diabetes (T1D) stereotype of the thin juvenile now overlaps Men with early-onset T1DA are more likely to transmit diabetes
with the type 2 diabetes (T2D) stereotype of the obese, insulin-resistant to their offspring compared with women (Fig. 71.2), but it is
adult. not clear whether this results from genomic imprinting of a gene
• In Caucasian children, the diagnosis of T1D can be made on the basis expressed only from a paternally inherited allele or other possible
of classic clinical features. reasons. The risk is also greater in later-born offspring. The peak
• The presence of islet autoantibodies confirms the diagnosis of type
1A diabetes (T1DA). age of incidence in children is at the cusp of puberty, a time
• Islet autoantibodies are present in more than 90% of Caucasian children when the body’s requirement for insulin increases along with
but in only about 50% of Hispanic or African American children, some an increase in insulin resistance. Like the seasonal autumn–winter
of whom have T2D. peak in diagnosis that is attributed to viral infections, this is
• Islet autoantibodies can be detected in the first 3 years of life in the likely to be “the straw that breaks the camel’s back” on a back-
majority of Caucasian children who go on to develop T1DA. ground of longer-standing autoimmune β-cell dysfunction.
• The risk for T1DA increases with the number and titer of islet
autoantibodies.
PATHOGENESIS: NATURE AND NURTURE
EPIDEMIOLOGY AND NATURAL HISTORY OF T1DA The model for the staged natural history of T1DA, arising from
16
the seminal studies of Eisenbarth, is illustrated in Fig. 71.3.
The incidence of T1DA varies widely across the globe, being Although the pattern and rate of β-cell loss is depicted as linear,
highest among Caucasians of northwestern Europe and countries it is more likely to be episodic, reflecting direct (e.g., virus,
to which they have emigrated (Fig. 71.1). This, in part, reflects chemical toxin) or indirect (e.g., diet, pollutants, microbiome)
CHaPter 71 Type 1 Diabetes 959
< 1.5 8.5 - 14 No data
1.5 - 5 14 - 24
5 - 8.5 > 24
FIG 71.1 Global Incidence of type 1A diabetes (T1DA) in 100 000 children ages 0–14 years per
year. (From IDF diabetes atlas, 7th ed. Brussels, Belgium: International Diabetes Federation;
2015.)
Type 1A diabetes lifetime risk
General population
5% 4% 0.25%
First-degree relative HLA high risk genes No HLA risk genes
(FDR)
3% 5% 8% 0.01%
Mother Father Sibling
Protective HLA allele
10–20%
FDR and HLA high risk genes 95% of caucasians cases have at least one
high risk HLA allele
FIG 71.2 Lifetime risk of type 1A diabetes.
interactions between the environment and β cells. In addition, which shares several key features with T1DA in outbred humans
evidence suggests that immune activation and β-cell destruction (Table 71.1) despite 65 million years of evolutionary distance.
may be accelerated in the late preclinical stage. The appearance The molecular mechanisms of β-cell death, gleaned mostly from
5
of predictive islet autoantibodies in the first years of life means the NOD mouse, encompass a combination of both apoptosis
that the stage for developing T1DA is set very early, even before induced by activation of extrinsic (e.g., tumor necrosis factor
birth, on a background of genetic susceptibility. These early years [TNF] receptor or Fas ligation) or intrinsic (e.g., endoplasmic
must provide clues to environment–gene interactions that lead reticulum [ER] stress) pathways and necroptosis induced by
to immune dysfunction and disease. cytotoxic CD8 T-cell granule components (granzymes and
It is generally agreed that β-cell destruction in T1DA is medi- perforin), reactive oxygen species (ROS), or ischemia.
ated by autoreactive T cells, the ultimate effectors being CD8 The evidence from human studies is obviously less compelling,
cytotoxic T cells (Fig. 71.4). The evidence for this is unequivocal as access to human pathology is limited. Studies of pancreas
in the inbred nonobese diabetic (NOD) mouse model of T1DA, biopsies and organ-donor pancreas, more recently from the
960 Part seven Organ-Specific Inflammatory Disease
Environmental modifiers
100%
Autoantibodies to
insulin, GAD65, IA2, ZnT8
Beta-cell function susceptibility Immune cells insulin response (iv glucose)
Loss of first phase
Loss of glucose
Genetic
tolerance (oral glucose)
invade
Pre-
the islets
beta-cell injury diabetes
Diabetes
Birth Months Years
Autoimmune disorder Metabolic disorder
FIG 71.3 Natural history of type 1A diabetes.
Activated cytotoxic
CD8 T cells
Pancreatic islet
β cell
β cell
CD8 T cells
Activated CD4
helper T cell
β cell TCR CD40L
antigen
CD40 TCR
MHC II
Pancreatic MCHI
lymph node
β cell
antigen
mimic Activated dendritic cell Super-activated dendritic cell
FIG 71.4 Immune mechanisms of β-cell destruction in type 1A diabetes.
Network for Pancreatic Organ Donors with Diabetes (nPOD; is driven by loss of immune tolerance to self-antigens. In the
www.jdrfnpod.org), have not revealed the florid immune cell case of T1DA, considerable evidence, direct in the NOD mouse,
infiltration of islets (insulitis) seen in NOD mice but rather identifies (pro)insulin as a key disease-initiating self-antigen
patchy insulitis predominantly caused by CD8 T cells and (Table 71.2).
macrophages. A further observation, confirming earlier observa-
17
tions, is hyperexpression of HLA class I by islets, in association GENES
with immunoreactive interferon-α (IFN-α), even in atrophic
islets lacking insulin, which can be taken as presumptive evidence The concordance for T1D in monozygotic twins, who are almost
for persisting virus. A key question is: why are β cells specifically totally genetically identical, approaches 50%, indicating that both
targeted? The answer may lie in insulin itself. Central to the genetic and environmental–epigenetic mechanisms contribute to
concept of autoimmune disease is the notion that the pathology disease. Large case/control studies and more recently genome-wide
CHaPter 71 Type 1 Diabetes 961
TABLE 71.1 the nonobese Diabetic T1DA but denotes susceptibility for a subtype of multiple sclerosis
(nOD) Mouse as a Model of Human type and for narcolepsy. The second most important contribution is
1a Diabetes from the insulin gene (INS) locus (IDDM2), which maps to a
variable number of tandem repeats (VNTR) 5’ of the coding
Feature nOD Mouse Human sequence. Apart from the HLA locus, IDDM2 is still the only locus
Preclinical stage Yes Yes for which genome-wide association is reflected by linkage, which
Gender F > M M > F after puberty might be explained by disease heterogeneity. Long (class III) and
Genetic susceptibility short (class I) variable number tandem repeat (VNTR) alleles
MHC class II fi57 non-Asp Yes (I-Ag ) Yes (HLA-DQ8) are associated, respectively, with higher and lower transcription
7
Polygenic non-MHC Yes Yes of proinsulin messenger RNA (mRNA) in medullary thymic
Environmental influence on Yes Yes epithelial cells (mTECs) under the control of the autoimmune
gene penetrance 20 21
Disease transmission via Yes Yes regulator gene (AIRE) and with lower and higher T1DA risk.
bone marrow This leads to the inference that IDDM2 controls the extent of
Mononuclear cell infiltration Marked Moderate deletion of proinsulin-specific T cells during their intrathymic
of islets (insulitis) development and predicts that the long VNTR would be associated
Other organs Yes Sometimes with less proinsulin-specific T cells in the periphery; there is
Impaired immune regulation Yes Yes evidence for and against this, perhaps because of the difficulty
Autoantigens: of measuring islet antigen-specific T cells in human blood. The
(Pro)insulin Yes Yes
Glutamic acid Yes Yes INS polymorphism is unique to humans. Mice, instead, have
decarboxylase (GAD) two insulin genes; INSI is expressed in the β cell and INSII in
Clinical response to Yes Not yet shown the thymus, and expression of the latter is impaired in the NOD
autoantigen-specific therapy mouse. In summary, IDDM2 provides a genetic mechanism for
autoimmunity targeting proinsulin and the β cell.
Many of the other candidate genes are involved in immune
function and are associated with other autoimmune diseases.
TABLE 71.2 evidence for the Key role of For example, a nonsynonymous gain-of-function (GOF) poly-
Proinsulin as Primary autoantigen in type morphism in PTPN22 (lymphoid tyrosine phosphatase) results
1a Diabetes (t1Da) in enhanced T-cell suppression, which may impair negative
• β cell–specific (except for thymus) selection of autoreactive T cells in the thymus and decrease the
• Second strongest genetic locus in humans (IDDM2) = VNTR 5’ of number and function of natural regulatory T cells (nTregs).
INS allelism correlates with proinsulin transcription in the thymus Polymorphisms around IL2RA (interleukin-2 [IL-2] receptor α
• Early target of autoimmunity in humans and nonobese diabetic chain; CD25) and IL2 are associated with impaired IL-2 signaling,
(NOD) mice which in both humans and NOD mice impairs the generation
• Main target of T cells isolated from islets of NOD mice and and maintenance of nTregs. Polymorphisms involving the VDR
humans with T1DA
Genetic manipulation in the NOD mouse: (vitamin D receptor) and CYP27B1 (25-hydroxyvitamin vitamin
• Transgenic expression of proinsulin (but not glutamic acid D3 1-α-hydroxylase) and IFIH1 (IFN-induced with helicase C
decarboxylase [GAD]) in antigen-presenting cells (APCs) prevents domain 1; which enhances the type I IFN response to virus
insulitis/diabetes infection) are clues to gene–environment interactions in T1DA.
• Transfer of hematopoietic stem cells (HSCs) or myeloid progenitors
encoding proinsulin in APC progeny prevents diabetes
• Knockout of proinsulin II (expressed in thymus) accelerates β CELLS
diabetes
• Induction of mucosal tolerance to (pro)insulin prevents diabetes Why are β cells selectively destroyed by immune inflammation
that involves the whole islet, which also contains a minority of
glucagon-secreting α cells and other endocrine cells? First,
cytotoxic CD8 T cells recognize autoepitope peptides (e.g., from
association (GWA) studies have identified over 40 chromosomal insulin) presented by hyperexpressed HLA class I proteins on β
loci associated with risk for T1DA 18,19 (Fig. 71.5). Many are weak cells. Second, because of their unique metabolic wiring, β cells
associations defined only by single nucleotide polymorphisms may contribute to their own death at the hands of the immune
(SNPs), and the genes with which the SNPs are in linkage and/or system. Evidence for the hypothesis of “assisted suicide” is
22
their functional contribution to pathogenesis are not known. It compelling. Studies of rodent islets, mainly in vitro, have
is likely that different combinations of genes/susceptibility loci in indicated that β cells lack efficient antioxidant and free radical
different environmental contexts lead by different routes to the scavenging mechanisms and are especially sensitive to mitochon-
final outcome of β-cell destruction and account for phenotypic– drial oxidative and ER stress in response to cytokines and
22
clinical heterogeneity in T1D. Nevertheless, what is clear across granzymes, although more recent studies of human islets do
23
populations globally is the dominance of the HLA locus (IDDM1) not support this view. Third, many of the candidate T1D genes
as the single most important genetic contributor to T1D risk identified in GWA studies are transcribed in β cells (see Fig.
23
(see Table 71.1), accounting for about half the lifetime risk. The 71.4) and encode proteins that interact with the immune system.
highest risk HLA haplotypes in Europeans are DR3 (DRB1*03:01- Finally, in response to inflammation, human islets generate
DQA1*05:01-DQB1*02:01) and DR4 (usually DRB1*04:01 or hundreds of RNA splice variants for proteins, which, translated
*04:04 with DQA1*03:01-DQB1*03:02). It should also be noted as neoantigens, may not be subject to immune tolerance.
that the HLA DQ6 haplotype DQA1*01:02-DQB1*06:02, which is Although it is still unclear whether human β cells are
in linkage with DR15 (DRB1*15:01), is dominantly protective for more sensitive than other autoimmune target cells to immune
962 Part seven Organ-Specific Inflammatory Disease
7.0
6.5
6.0
Odds ratio 5.5
2.5
2.0
1.5
1.0
HLA *INS PTPN22 IL2RA C10orf59 *SH2B3 *ERBB3 *COBL *PTPN2 *CTRB1/2 *CLEC16A CTLA4 IL18RAP PTPN2 IL10 CCR5 *C6orf173 *C14orf181 *PRKD2 *IFIH1 *CTSH CD226 IL27 GAB3 IL2RA *SKAP2 *GLIS3 *ORMDL3 *PRKCQ IL2 BACH2 UBASH3A *RGS1 IL7R CIQTNF6 SIRPG *TNFAIP3 4p15 CD69 14q22 TAGAP *SMARCE1
Locus
FIG 71.5 Candidate genes in type 1A diabetes (T1DA). The y-axis shows the odds ratio for risk
alleles at each of the loci on the x-axis. The majority of the known genes are involved in immune
18
responses, and many (marked *) are expressed in islets. Colors indicate era of identification:
blue 1970–2000; green 2001–2006; red 2007–2008; yellow 2009–2010.
effectors, what is clear is that having undergone apoptotic or and by promoting obesity and insulin resistance and thereby
necrotic death, β cells are not restorable in the face of autoimmune increasing the workload of the β cell.
memory. The environment in Western societies has changed dramatically
in many ways during the last century (Fig. 71.6), and some of
KeY COnCePts these changes have been associated epidemiologically or in animal
6
Type 1A Diabetes Is an Autoimmune Disease studies with development of T1DA. An index of the modern
“exposome” is the ongoing rise in the prevalence of obesity.
• Genetic and familial clustering, as well as association with other When children at increased genetic risk for T1DA (with an affected
autoimmune diseases, including autoimmune polyendocrinopathy first-degree relative) were monitored from birth, weight gain in
syndromes (e.g., APS-1 due to mutations in AIRE) the first 2–3 years of life was shown to be a risk factor for islet
• Presence of autoantibodies and T cells reactive with islet cell autoimmunity. When such at-risk children developed islet
24
antigens autoantibodies and were then followed up over time, those with
• Strong association with specific human leukocyte antigen (HLA) alleles insulin resistance progressed most rapidly to clinical diabetes.
15
and haplotypes
• Transfer of disease by bone marrow or development of disease in Whether insulin resistance is a risk factor for the development
normal pancreas transplanted from identical twin without diabetes to of islet autoimmunity is an open question that should be answered
25
the twin with diabetes by ongoing pregnancy–birth cohort studies. If insulin resistance
• Neonatal onset with loss of natural regulatory T cells with mutations synergizes with impaired insulin secretion to promote T1DA,
in FOXP3 (immune dysfunction/polyendocrinopathy/enteropathy/X-linked then lifestyle factors must be considered in the efforts to forestall
[IPEX] syndrome) or prevent T1DA.
Excessive energy consumption leading to obesity is part of a
ENVIRONMENT—OUTSIDE AND INSIDE complex interplay of related factors that promote low-grade
inflammation and insulin resistance. These include a poor-quality
The environment in its various manifestations may impact on diet and lack of physical exercise, sunlight (vitamin D), and
β-cell function in several possible ways: by activating innate sleep. The highly processed fast-food “Western” diet lacks diversity
immune cells (macrophages) in the islets to release cytokines of components, lacks plant-derived prebiotics and complex
(e.g., IL-1β, TNF) that elicit mitochondrial oxidative ER stress; carbohydrates (starches and fiber), is high in saturated fats and
by driving adaptive immunity to β cells in people with T1D risk in sucrose and fructose sugars, and has added artificial preserva-
genes, either generally or specifically by inducing posttranslational tives, emulsifiers, and sweeteners. All of these alter the composition
modifications in β-cell proteins that render them immunogenic; of the gut microbiome and reduce its diversity, which is a feature
CHaPter 71 Type 1 Diabetes 963
The Environment
Th he e e E
T T T Th
h h has
has Changed
Excess calories *
Different, less diverse food
Less physical activity *
Less sunlight-vitamin D *
More ‘hygiene’ *
Fewer infections
More C-sections *
Less breast milk *
More antibiotics *
Less thermoregulation
Less sleep
More pollution
Modifiers: culture,
education, wealth, access
to technology, family size,
maternal age...
FIG 71.6 Changes in the modern environment. Those that have been associated with an increased
risk for type 1A diabetes (T1DA) in humans or nonobese diabetic (NOD) mice are indicated
(marked *).
31
26
found in children at risk for T1DA. Diets containing a diverse enteroviruses in T1DA but has not been consolidated in follow-
range of plant products (cereals, fresh fruits, and vegetables) up studies. Even if a particular enterovirus strain were shown
provide complex carbohydrates for fermentation by colonic directly to be diabetogenic, vaccination would be elusive because
bacteria to short-chain fatty acids (SCFAs), which are antiinflam- among the many thousands of strain variants, the only one for
27
matory. The dramatic influence of the environment is seen in which a vaccine exists is poliovirus. Mumps virus epidemics
the comparison between the highly developed Finland and the have been associated with T1DA onset after 2–4 years, and
nearby undeveloped Russian Karelia. Finland has the highest introduction of a mumps vaccine was associated with a plateau
incidence of T1DA in the world, currently 57.6 cases/100 000 in the rising incidence of T1D in Finland, but this was temporary,
population ≤14 years of age (www.diabetesatlas.org). In 2005, and mumps vaccination has clearly not prevented T1D. It must
there was a sixfold difference in the incidence of T1DA between be emphasized that there is no scientific evidence that any form
Finland and Karelia despite overlap in ethnic background and of vaccination itself triggers T1DA.
28
a similar distribution of HLA-DQ risk genotypes. This difference Rotavirus is the commonest cause of gastroenteritis in young
could reflect a relatively lower rate of infections (in Finland), in children. The discovery of strong sequence similarities between
keeping with the “hygiene hypothesis.” 29 T-cell epitopes in the VP7 protein of rotavirus and the IA2 and
However, viral infections have long been considered triggers GAD islet antigens in autoantibody-positive children led to
of T1DA, but the evidence remains inconclusive. 30,31 Viral infection speculation that mimicry of rotavirus might contribute to islet
is circumstantially associated with the onset of T1DA, but given autoimmunity. Subsequently, in the Australian BabyDiab Study,
the long presymptomatic stage of the disease, this may simply rotavirus infection was associated over time with the first appear-
represent a nonspecific inflammatory insult that precipitates ance of or an increase in islet autoantibodies in children before
33
clinical presentation. Viral mechanisms in T1DA could be direct they developed diabetes. Moreover, rotavirus has been shown
or indirect (e.g., infection of β cells, infection of the exocrine to infect β cells in islets from mice, pigs, and monkeys and cause
pancreas with bystander death of β cells, mimicry between T-cell transient involution of the pancreas and hyperglycemia in a
34
epitopes in a viral protein and β-cell autoantigens, or activation Toll-like receptor 3 (TLR3)–dependent manner in mice.
of endogenous retroviruses in β cells by environmental agents). Ubiquitous rotavirus infections that drive cross-reactive immunity
If an exogenous virus was clearly identified, then protective to islet autoantigens are unlikely to be diabetogenic but could
vaccination early in life would be an approach to primary preven- complement and sustain the immune response to direct infection
tion. Interest in viral triggers of T1DA was initiated by the of β cells. As with rubella and mumps, it will be interesting to
observation that a minority of children with congenital rubella observe if recently introduced rotavirus vaccines have any effect
32
developed insulin-dependent diabetes and were found to have on the incidence of T1DA.
a higher frequency of what was later recognized as the T1D The microbiome—the trillions of microorganisms (bacteria,
susceptibility haplotype HLA-A1 B8-(DR3-DQ2). Clearly, this fungi, archaea, protozoa, and viruses; Chapter 14) and their
may have been an anomaly because congenital rubella has been millions of genes and proteins that reside within the human
virtually eliminated by vaccination and yet the incidence of T1D mucosae, skin, and secretions—has gained increasing atten-
has continued to climb. Much circumstantial evidence exists for tion as a bellwether of health and disease (“dysbiosis”). Most
964 Part seven Organ-Specific Inflammatory Disease
microbiome analyses are based on DNA extraction and poly- on a limited scale and at considerable cost to individuals with
merase chain reaction (PCR) amplification of regions of the 16S T1DA and life-threatening complications, in particular lack of
ribosomal RNA (rRNA) gene that are conserved among bacteria. awareness of hypoglycemia that is unresponsive to conventional
Although other internal regions of the 16S gene are variable treatment. However, shortage of donor tissue, cost, and the need
and enable taxonomic classification from the phylum to genus for life-long immune suppressive agents militate against this
level, 16S sequencing does not have the sensitivity to distinguish solution. Longer-term, genetically engineered pig islet xenografts
individual species and their strains. Direct metagenomic sequenc- may overcome the tissue supply barrier. Stem cells, in particular
ing of all species, as well as analysis of their transcriptomes, autologous induced pluripotent stem cells (iPSCs), remain the
epigenomes, and functions, is required to fully comprehend the great hope, but early proof-of-concept results in rodents await
role of the microbiome in T1DA and other chronic immune– scale-up and translation to humans.
inflammatory diseases. The marked difference in the incidence The incidence of spontaneous autoimmune diabetes in
of T1DA between Finland and neighboring Karelia was found inbred NOD mice is decreased by many immune and other
to be associated in Finnish children having decreased bacterial (including environmental) interventions introduced early in the
diversity overall, a dominance of the phylum Bacteroidetes, and disease course, although various interventions are often only
26
lack of butyrate-producing bacteria. These changes were seen effective in a proportion of mice, sometimes only delay disease
after the appearance of autoantibodies, suggesting that they onset, and sometimes have no effect (and are therefore not
followed, rather than preceded, the disease process. However, reported). Nevertheless, these findings in the NOD mouse suggest
in a further small study in Finnish children, metagenomic that T1DA is potentially preventable in outbred humans. On
sequencing identified a relative abundance of Bacteroides dorei, the basis of the key role of proinsulin in driving β-cell autoim-
which peaked around 7–8 months of age with the introduction of munity, the NOD mouse has provided “proof-of-concept” for the
35
solids and preceded the appearance of islet autoantibodies. Gut efficacy of antigen-specific vaccination strategies. In humans,
Bacteroides species are abundant in Finnish children, including it has been convenient to classify prevention into primary
B. dorei, which produces a lipopolysaccharide (LPS) endotoxin (before the onset of islet autoimmunity), secondary (after
that inhibits the immunostimulatory activity of Escherichia coli the onset of islet autoimmunity), and tertiary (after the onset
LPS, known to protect against development of diabetes in NOD of clinical disease) prevention. Of course, real prevention is
mice. These findings suggest that an approach to lowering the primary prevention—identifying those at genetic risk and inter-
environmental contribution to T1DA will be intervention with vening to avert islet autoimmunity. Neonatal screening based
prebiotics, probiotics, or other means to favorably alter the on HLA genotyping to identify at-risk individuals would be
composition of the gut microbiome. a basis for primary prevention, but even in countries with a
high incidence of T1DA, this would have only modest predictive
KeY COnCePts value, and intervention could be justified if it was practical and
Type 1A Diabetes: Epidemiology, Environment, safe, if not efficacious. The mandate Primum non nocere (“first
do no harm”) dictates that many immune modulating agents
and Genes are off limits for either primary or secondary prevention in
• Incidence is increasing as a result of the impact of environment. T1DA. Options (e.g., to modification of the diet or microbi-
• Environment factors enable increasing penetrance of lower-risk human ome or of forms of vaccination) are greatly restricted. Agents
leukocyte antigen (HLA) alleles. that are effective in other autoimmune diseases are more
• Environmental factors are multifactorial but generally “pro-inflammatory” likely to be effective in the early asymptomatic stage of T1DA,
and impact via microbiome dysbiosis and epigenetic modifications on not after clinical presentation when most β cells have been
polygene expression to cause immune dysregulation in early life. destroyed. Indeed, clinical trials of tertiary prevention with
more than 70 different agents since the early 1980s have failed
TREATMENT AND PREVENTION to unequivocally demonstrate sustained preservation of residual
β-cell function. 36,37 Interestingly, the number of trials reporting a
Treatment of the metabolic syndrome of T1D is focused on positive outcome decreased from the 1980s, together with a shift
optimizing blood glucose control with various modes of insulin in the primary outcome measure away from clinical remission
delivery to prevent the short- and long-term complications of to the more rigorous measure of residual insulin (stimulated
hyperglycemia. Refinements and advances over the past 30 years C-peptide) secretion.
in insulin delivery and improved control of blood glucose and Is there a potential solution to the “off limits” dilemma? Classi-
blood pressure have greatly improved the lives and prognosis of cally, T1DA is regarded as a metabolic disorder diagnosed at clinical
individuals with T1DA. Nevertheless, despite the introduction presentation with symptoms and signs of hyperglycemia. However,
of pure, recombinant forms of human insulin, which have varied based on pathology, T1DA is an immune disease—autoimmune
kinetics of action and can be injected via a syringe or continuously β-cell disorder (ABCD)—and only becomes a metabolic disorder
infused via a pump, and blood glucose self-monitoring, which at the end stage of its pathology. Accepting this reality would
can now be done continuously in real time, those with T1DA amount to a paradigm shift that could profoundly change the
have not been rescued from a life sentence, and their blood approach to and outcome of secondary prevention. Consider the
glucose control remains less than physiological. The “cure” of situation in other autoimmune diseases. In rheumatoid arthritis,
T1DA requires the transplantation of insulin-secreting cells or the pathology and clinical features (painful swollen joints) appear
their progenitors or the regeneration of β cells in situ, in conjunc- concomitantly when effective disease-sparing treatment with
tion with approaches to prevent allograft rejection and/or newer biological agents is initiated, not at the end stage of pathol-
recurrence of autoimmunity (there will be no cure for T1DA ogy when the joints are irreversibly deformed. A further benefit
without prevention). Currently, in some economically developed of diagnosing of T1DA early in the asymptomatic stage, based
societies, allografts of whole pancreas or isolated islets are offered on evidence of underlying pathology, is that it would markedly
CHaPter 71 Type 1 Diabetes 965
reduce the risk of life-threatening ketoacidosis associated with daily) did not alter the rate of progression to diabetes in islet
the classic symptomatic presentation. autoantibody-positive children <3 years of age. However, these
In health, immune responses to autoantigens are regulated children were at very high risk, and many appeared to have had
to prevent development of autoimmune diseases. Autoantigen- borderline β-cell function. As in the oral insulin trial, markers
specific immunotherapy aims to boost or restore autoantigen- of an insulin bioeffect and evidence of immune tolerance were
specific immunoregulatory mechanisms. Its parallel, allergen-specific not reported. In the ongoing Intranasal Insulin Trial II (INIT
immunotherapy, has been shown in randomized trials to be effective II) in Australia, New Zealand, and Germany, higher doses of
in allergic asthma and rhinitis. Such “negative vaccination” can nasal insulin (44 or 440 IU) are being administered weekly for
be achieved in several ways: by administering antigen via a a year to relatives with T1D who have autoantibodies to at least
“tolerogenic” route (mucosal, dermal), cell type (resting dendritic two islet antigens (≈40% risk of diabetes over 5 years). The
cell), mode (with blockade of costimulation molecules), or form primary outcome is clinical diabetes; secondary outcomes are
(as an “altered peptide ligand”). Mechanisms of antigen-induced measures of metabolic and immune function. In INIT II, the
tolerance include deletion and/or anergy of effector T cells and insulin dose is substantially higher than in the Finnish study,
induction of regulatory T cells (iTregs). Of clinical importance is the participants are older and have less advanced subclinical
the ability of iTregs to exert antigen nonspecific “bystander” sup- disease and therefore are at lower risk. The promise of antigen-
pression. Thus by direct cell contact and/or the release of soluble specific therapy, therefore, has yet to be realized in humans. If
immunosuppressive factors, such as IL-10, iTregs impair the a balance between pathogenic and protective T cells is deter-
function of antigen-presenting DCs to elicit effector T-cell responses ministic for disease development, then antigen-specific therapy
to the same or other antigens presented locally in the lesion or is most likely to be effective as a primary preventive strategy.
draining lymph nodes. Bystander suppression does not require Once disease has been initiated, insulin-specific or other antigen-
that the “tolerizing” antigen is necessarily the primary driver of specific approaches may require complementary therapy with
pathology. Its clinical importance is that it obviates specificity other agents to inactivate or delete the burden of pathogenic
restrictions imposed by polymorphisms in the HLA and human effector cells.
T-cell receptors.
In NOD mice, administration of insulin, proinsulin peptides, On tHe HOrIZOn
or proinsulin DNA via oral or nasorespiratory routes, acting
locally on the mucosal immune system, induces Tregs and • Closed-loop insulin delivery—blood glucose monitoring devices will
become more refined, cheaper, and widely available.
decreases the incidence of diabetes. Results of randomized second- • “Linking the -omes” (exposome–microbiome–metabolome–epigenome)
ary prevention trials of insulin or GAD in relatives at risk for across time in early life will provide new insights into how environ-
T1DA (ClinicalTrials.gov) have been summarized elsewhere. 35-37 ment–gene interactions lead to immune dysregulation and type 1A
In the DPT-1 oral insulin trial, relatives with a 5-year diabetes diabetes (T1DA).
risk of 25–50% received 7.5 mg human insulin or placebo daily • Manipulation of the gut microbiome via scientifically formulated probiot-
for a median of 4.3 years. There was no effect overall, but posttrial ics and prebiotics will be used for primary prevention of T1DA.
hypothesis testing revealed a significant delay in diabetes onset • T1DA is primarily an immune disease—autoimmune β-cell disorder
(ABCD)—and only secondarily a metabolic disorder. Recognition of
38
in participants with significant IAA at entry. This outcome has these disease components will expand the therapeutic possibilities
led to an ongoing follow-up international trial by NIH-TrialNet for secondary prevention.
using the same dose of 7.5 mg daily, which is not optimal because
on a body-weight basis this dose is very small compared with
that required to induce protective iTregs in the NOD mouse. Please check your eBook at https://expertconsult.inkling.com/
Apart from the dose, other variables have not been systemati- for self-assessment questions. See inside cover for registration
cally tested in humans, in part because of the expense and duration details.
of prevention trials. These variables include route of administra-
tion, form of the antigen, combinations of antigen with antigen- REFERENCES
nonspecific agents, and the nature of induced immune responses.
Unfortunately, surrogate markers of a potential therapeutic 1. The Expert Committee on the Diagnosis and Classification of Diabetes
response have not been included in most trials and, in the case Mellitus. Report of the expert committee on the diagnosis and
of antigen-specific T cells in blood, are not universally accepted classification of diabetes mellitus. Diabetes Care 2003;26:S5–20.
as being sufficiently robust and reproducible. Oral delivery might 2. Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in
first-degree relatives using a combination of insulin, GAD, and
not be optimal because proteins are degraded after ingestion, ICA512bdc/IA-2 autoantibodies. Diabetes 1996;45:926–33.
and the concentration or form of peptide reaching the upper 3. Colman PG, Steele C, Couper JJ, et al. Islet autoimmunity in infants with
small intestine may be variable and unpredictable. T-cell responses a type I diabetic relative is common but is frequently restricted to one
that were observed after nasorespiratory administration of a autoantibody. Diabetologia 2000;43:203–9.
peptide have not been observed after oral administration. In a 4. Bingley PJ, Williams AJ, Gale EA, et al. Optimized autoantibody-based
randomized trial of nasal insulin in individuals with recent-onset risk assessment in family members. Implications for future intervention
T1D not initially requiring insulin treatment, participants in trials. Diabetes Care 1999;22:1796–801.
the nasal insulin arm had markedly blunted insulin antibody 5. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet
39
responses after subsequent subcutaneous insulin. This was the antibodies and risk of progression to diabetes in children. JAMA
2013;309:2473–9.
first demonstration, in humans, of immune regulation induced 6. Wentworth JM, Fourlanos S, Harrison LC. Deconstructing the stereotypes
by mucosally administered exogenous autoantigen. Although of diabetes within the modern diabetogenic environment. Nat Rev
this result provides a rationale for further disease endpoint trials, Endocrinol 2009;5:483–9.
40
a Finnish study suggested that this result cannot be extrapolated 7. Fourlanos S, Dotta F, Greenbaum CK, et al. Latent autoimmune diabetes
to endogenous “autoantigenic” insulin. Nasal insulin (1 unit/kg in adults (LADA) should be less latent. Diabetologia 2005;48:2206–12.
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