The Netter Collection of Medical Illustrations VOLUME 2_Endokrinnaya_sistema

Plate 5-10 Endocrine System

DIABETIC KETOACIDOSIS Circulation Glucose cannot freely enter Adipose tissue
Glucose muscle or fat cells in
Diabetic ketoacidosis (DKA) is serious complication of absence of insulin P
diabetes mellitus characterized by the triad of hyperg- Deficiency
lycemia, anion gap metabolic acidosis, and ketonemia. of P-glycerol
DKA results from severe insulin deficiency with result-
ant hyperglycemia, excessive lipolysis, increased Albumin Fatty acid CO2
fatty acid oxidation, and excess ketone body production. Fatty acid mobilized ϩ
The deficiency of insulin and the excess secretion of Large H2O
glucagon, catecholamines, glucocorticoids, and growth amounts of Fatty acid
hormone stimulate glycogenolysis and gluconeogenesis fatty acid
while simultaneously impairing glucose disposal. DKA taken up Fatty acids
is primarily a complication of type 1 diabetes mellitus by liver liberated from
because it is usually only seen in the setting of severe triglyceride
insulin deficiency. DKA may be the initial presentation Ketone
of new-onset type 1 diabetes mellitus. accumulation Liver
in blood
Most patients with DKA have preceding symptoms exceeds amount Triglyceride
of polyuria, polydipsia, and weight loss that result from utilizable by
a partially compensated state. However, with absolute muscle and CH3CO CoA CH3COCH2CO CoA Fatty acid
insulin deficiency, metabolic decompensation can inter- organs Acetyl CoA Acetoacetyl CoA Fatty
vene rapidly over 24 hours. Typical DKA presenting
symptoms include nausea; emesis; abdominal pain; Na Acetyl CoA infiltration
lethargy; and hyperventilation with slow, deep breaths Na HCO3 Ketones exceeds
(Kussmaul respirations). On physical examination, most amount OH of liver
patients with DKA have a low-normal blood pressure, H2O utilizable CH3ϪC Ϫ CH2CO CoA
increased heart rate, increased respiratory rate, signs of ϩ by Krebs
volume depletion (e.g., decreased skin turgor, low CO2 Ketones CϩO2 CH2
jugular venous pressure, and dry oral mucosa), and Ketones combine ___H2O
breath that smells of acetone (a fruity odor similar to with base
nail polish remover). With profound dehydration, of plasma cycle COOH CH3CO CoA
patients may be obtunded or comatose. Acetyl CoA

The laboratory profile in patients with DKA in- CH3COCH2COOH ␤-hydroxy-
cludes low serum bicarbonate (HCO3) concentration Acetoacetic acid ␤-methyl-
(<10 mEq/L); increased serum concentrations of ke- glutaryl CoA
toacids (acetoacetate, β-hydroxybutyrate); increased
anion gap (calculated by subtracting the sum of the CH3CHOH CH2COOH Muscle
serum concentrations of chloride and bicarbonate from ␤-hydroxybutyric acid
that of sodium; reference range, <14 mEq/L; DKA
usually >20 mEq/L); increased serum glucose con- Kidney Acetoacetic acid
centration (500–900 mg/dL); and decreased arterial
pH (<7.3). Base, calories, Acetyl CoA Krebs
and H2O lost CO2 cycle
The differential diagnosis of DKA includes other in urine ϩ
causes of metabolic acidosis (e.g., lactic acidosis, starva- H2O
tion ketosis, alcoholic ketoacidosis, uremic acidosis, and
toxin ingestion [e.g., salicylate intoxication]). Lung

TREATMENT Ketoaciduria Brain

Keys to successful outcomes in DKA are prompt rec- Acidosis Hyperventilation (Kussmaul respirations) Coma
ognition and management. The three main thrusts of Dehydration and hyperosmolar state
treatment are fluid repletion, insulin administration,
and management of electrolyte abnormalities. All correction from the hyperosmolar state). With volume blood parameters should be monitored every 2 hours
patients with DKA have some degree of volume con- repletion, resolving acidosis, and improving blood (e.g., calcium, magnesium, and phosphate). DKA can
traction, which contributes to decreased renal clearance glucose concentrations, an underlying potassium deficit be corrected in most patients over 12 to 36 hours.
of ketone bodies and glucose. Most patients with DKA usually becomes evident and should be replaced when
should be treated with 1 L of normal saline over the the serum potassium concentration decreases below It is important to address the cause of DKA. The
first hour followed by 200 to 500 mL per hour until 5.3 mEq/L. most common cause is noncompliance with insulin
volume repletion. The rate and type of volume reple- therapy in a patient with known type 1 diabetes melli-
tion should be guided by clinical and laboratory Most patients with DKA should be admitted to an tus. Underlying infection (e.g., pneumonia, meningitis,
responses. Insulin should be administered intravenously intensive care unit setting in the hospital to facilitate or urinary tract infection) or severe illness (e.g., myo-
to avoid slow absorption from hypoperfused subcutane- close monitoring with continuous electrocardiography cardial infarction, cerebrovascular accident, or pancrea-
ous tissues. Insulin is usually started with a 10-U and hourly measurement of blood concentrations of titis) may be a trigger for DKA in a patient with type 1
priming dose and followed by a low-dose continuous glucose, potassium, chloride, and bicarbonate. Other diabetes.
infusion (e.g., 0.1 U/kg body weight/h). Serum glucose
usually decreases by 50 to 75 mg/dL per hour. As the
serum glucose concentration decreases to approxi-
mately 200 mg/dL, the insulin infusion rate should be
decreased so that hypoglycemia and cerebral edema are
avoided (the latter can result from too rapid a

138 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-11 Pancreas

ISLET CELL PATHOLOGY IN DIABETES

TYPE 1 DIABETES MELLITUS

The diagnosis of diabetes mellitus is established when Partial hyalinization Complete hyalinization
a patient presents with typical symptoms of hypergly- (Mallory aniline blue stain) (Mallory aniline blue stain)
cemia (polyuria, polydipsia, weight loss) and has a
fasting plasma glucose concentration of 126 mg/dL or Fibrosis Cordlike formation
higher or a random value of 200 mg/dL or higher, (Mallory aniline blue stain) (Mallory aniline blue stain)
which is confirmed on another occasion. There are
three general types of diabetes: type 1, type 2 (see Plate Hydropic change (vacuolization) Glycogen demonstrated in vacuoles
5-12), and gestational (see Plate 5-19). Type 1 diabetes (Gomori aldehyde fuchsin and Ponceau stain) by periodic acid–Schiff reagent
mellitus affects less than 10% of all patients diagnosed
with diabetes. Type 1 diabetes mellitus is the result of termed the honeymoon period. Eventually, the viability of CLINICAL PRESENTATION
pancreatic β-cell destruction; in more than 95% of the the remaining β-cells is exhausted. Sustained hyperglycemia that exceeds the renal thresh-
cases, it has an autoimmune basis caused by an apparent old for glucose reabsorption causes an osmotic diuresis,
selected loss of immune tolerance. If untreated, type 1 Histopathology studies from the 1960s showed that resulting in polyuria and polydipsia. The hyperosmolar
diabetes is a fatal catabolic disorder (see Plate 5-10). hydropic changes (vacuolization) were the initial step in state may also cause blurred vision caused by osmolar
Because of absolute insulin deficiency, all persons with islet destruction. This change was actually attributable impact on lens and retina. Weight loss is caused by
type 1 diabetes require insulin replacement therapy. to infiltration with glycogen as shown with periodic depletion of water, glycogen, fat, and muscle. Volume
acid–Schiff reagent. There is a selective destruction of depletion may cause postural lightheadedness. Par-
Immune-mediated type 1 diabetes is most common β-cells. At the time of clinical presentation, a chronic esthesias are a result of neurotoxicity from sustained
in northern Europe, where the approximate annual inflammatory infiltrate of the islets is present (insulitis). hyperglycemia. As insulin deficiency becomes nearly
incidence is 30 per 100,000 persons. The lowest inci- The inflammatory infiltrate consists primarily of T complete, the signs and symptoms of diabetic ketoaci-
dence of type 1 diabetes is in China (one per 100,000 lymphocytes (CD8 cells outnumber CD4 cells). Even- dosis predominate (see Plate 5-10).
persons per year). The peak life stage of onset is in tually, the islets become hyalinized, a process that par-
children or young adults. The offspring of a mother tially or completely replaces an islet.
with type 1 diabetes have a 3% risk of developing dia-
betes; the offspring of a father with type 1 diabetes have
a 6% risk. Environmental factors (infectious or toxic
environmental insult) have a major role in disease
development; only 50% of identical twins of type 1
diabetic patients develop diabetes. Individuals with
certain human leukocyte antigen (HLA) types are pre-
disposed to type 1 diabetes. HLA class II molecules DQ
and DR code for antigens expressed on the surface of
B lymphocytes and macrophages. Approximately 95%
of individuals with type 1 diabetes have HLA-DR3,
HLA-DR4, or both, findings present in 50% of nondia-
betic control subjects. Some DQ alleles (e.g., HLA-
DQA1*0102, HLA-DQB1*0602) are associated with a
decreased risk of diabetes. Non-HLA genes also affect
susceptibility to type 1 diabetes. For example, polymor-
phisms in a lymphocyte-specific tyrosine phosphatase
(PTNN22) and in a promoter of the insulin gene are
associated with an increased risk of type 1 diabetes.

The immune system mistakenly targets β-cell pro-
teins that share homologies with viral or other foreign
peptides, a concept termed molecular mimicry. Most
patients with newly diagnosed type 1 diabetes have cir-
culating antibodies (islet cell antibody, antibody to
glutamic acid decarboxylase [GAD], antibody to tyro-
sine phosphatases [insulinoma-associated protein 2],
cation efflux zinc transporter, or insulin autoantibody).
GAD is an enzyme in pancreatic β-cells that has homol-
ogy to coxsackievirus B.

The autoimmune destruction of β-cells progresses
over months and years, during which time affected indi-
viduals are euglycemic and asymptomatic (termed the
latent period). Impaired glucose tolerance usually pre-
cedes the onset of overt diabetes. By the time patients
come to clinical attention, they have lost more than
90% of their β-cell mass. The progressive hypergly-
cemia has a toxic effect on the remaining islets with
increased rate of apoptosis and impaired insulin secre-
tion. These toxic hyperglycemic effects can be reversed
over the short term with exogenous insulin treatment;
the pancreas seems to recover for a period of time,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 139

Plate 5-12 Endocrine System

TYPE 2 DIABETES MELLITUS Pancreas

The diagnosis of diabetes mellitus is established when Inadequate insulin secretion
a patient presents with typical symptoms of hyperglyc-
emia (polyuria, polydipsia, weight loss) and has a fasting Insulin receptor
plasma glucose concentration of 126 mg/dL or higher downregulation
or a random value of 200 mg/dL or higher confirmed
on another occasion. In asymptomatic individuals, the Insulin receptor
finding of fasting plasma glucose concentrations higher downregulation
than 126 mg/dL on more than one occasion is diagnos-
tic of diabetes. Individuals with fasting glucose levels Muscle Glucose cannot freely Triglyceride
from 100 to 125 mg/dL are considered to have impaired Protein enter muscle or fat cells
fasting glucose. Individuals with plasma glucose con- in absence of insulin Fatty acid
centrations at or above 140 mg/dL, but not over Amino Adipocyte
200 mg/dL, 2 hours after a 75-g oral glucose load are acids OO
considered to have impaired glucose tolerance.
Glucose Glucose
There are three general types of diabetes—type 1
(see Plate 5-11), type 2, and gestational (see Plate 5-19). O Glucose O
Type 2 diabetes mellitus accounts for more than 90% accumulates
of patients diagnosed with diabetes. Unlike type 1 dia- Glucose in blood Glucose
betes, in which the individual has an absolute insulin
deficiency, individuals with type 2 diabetes have a rela- OO
tive insulin deficiency in part because of a resistance to
insulin action. Most patients with type 2 diabetes are Glucose Glucose
obese and are diagnosed after the age of 30 years.
Liver
Insulin resistance in patients with type 2 diabetes is
related to polygenic factors, abdominal visceral obesity, O
sedentary lifestyle, and aging. Approximately 40% of
patients with type 2 diabetes have a least one parent Glucose
with the disorder. The concordance of type 2 diabetes
in monozygotic twins is 90%. Although many genetic Glycogenolysis
factors are yet to be discovered, several common genetic
polymorphisms increase the risk for type 2 diabetes. Glycogen
The basic pathogenesis of type 2 diabetes is inadequate
pancreatic β-cell insulin secretory response for the pre- the young (MODY), resulting in a defect in glucose- expression. For example, MODY 3 (the most common
vailing blood glucose concentration. Sustained hyperg- induced insulin release. These individuals are usually form of MODY) and MODY 1 are caused by mutations
lycemia magnifies the underlying insulin resistance and not obese and are diagnosed with diabetes in late child- in the gene that encodes hepatocyte nuclear factor 1α
β-cell dysfunction, both of which improve with treat- hood or as young adults. Six types of autosomal domi- (HNF-1α) and HNF-4α, respectively. MODY 4 is
ment and improved glycemic control. The impaired nant MODY have been described. MODY 2 is caused caused by mutations in insulin promoter factor-1 (IPF-
insulin secretion in patients with type 2 diabetes is by impaired conversion of glucose to glucose 6- 1), which mediates insulin gene transcription and regu-
multifactorial but is partly attributable to decreased phosphate in the β-cell because of a mutation in the lates other β-cell genes (e.g., glucokinase and glucose
β-cell mass associated with increased β-cell apoptosis. gene encoding the glucokinase enzyme. Glucokinase transporter 2). MODY 5 is caused by mutations in the
serves as a glucose sensor in the β-cell. The other gene encoding HNF-1β, and MODY 6 is caused by
Obesity (body mass index [BMI] >30 kg/m2) is forms of MODY are caused by mutations of genes that mutations in the gene encoding islet transcription
present in 80% of individuals with type 2 diabetes that encode transcription factors that regulate β-cell gene factor neuroD1.
are of European, North American, or African descent.
Only 30% of individuals with type 2 diabetes of Japa-
nese and Chinese descent are obese. The combination
of abdominal obesity, hyperglycemia, hyperinsuline-
mia, dyslipidemia, and hypertension has been referred
to as the metabolic syndrome (see Plate 7-15). Abdominal
obesity aggravates insulin resistance that results in
hyperglycemia leading to further hyperinsulinemia.
Type 2 diabetes occurs when the hyperinsulinemia is
insufficient to correct the hyperglycemia.

Diffuse damage to more than 70% of the pancreas
can cause diabetes. Examples of such insults include
pancreatitis, trauma, pancreatic carcinoma, hemochro-
matosis, and partial pancreatectomy. Excess production
of the four insulin counterregulatory hormones can
also cause diabetes. For example, diabetes may be the
initial presentation of the following endocrine disor-
ders: pheochromocytoma (catecholamines), acromegaly
(growth hormone), glucagonoma (glucagon), and
Cushing syndrome (glucocorticoids). Patients with thy-
rotoxicosis or somatostatinomas may also have diabetes.
The hyperglycemia in patients with these endocrinopa-
thies typically is cured by effective treatment of the
underlying disorder.

Approximately 5% of individuals with type 2 diabetes
have a monogenic disorder, maturity-onset diabetes of

140 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-13 Pancreas

DIABETIC RETINOPATHY Nonproliferative retinopathy

Moderate venous
distention and irregularity Dot and blot hemorrhages

Diabetic retinopathy, a microvascular complication of Hard Microaneurysms
chronic hyperglycemia, causes a 25-fold increased inci- exudates
dence of blindness in patients with diabetes compared
with the general population. Vision loss is caused by Scattered Cotton wool patches
retinal hemorrhage, macular edema, retinal detach- microaneurysms (retinal infarcts)
ment, or neovascular glaucoma. Patients with both type
1 and type 2 diabetes are at risk of developing diabetic Flame-shaped hemorrhages Vascular leakage in macular area
retinopathy. Nearly all patients with type 1 diabetes and Fluorescein angiograms
more than 50% of patients with type 2 diabetes develop Proliferative retinopathy
some degree of retinopathy within 20 years of their
diagnosis. IRMA Neovascularization
located >1 DD from optic disc (NVE)
The pathogenesis of diabetic retinopathy is complex
and related to abnormal retinal vessel permeability Venous
and vascular occlusion with ischemia. The retina is loop
exquisitely sensitive to both ischemia and substrate
imbalance. Chronic hyperglycemia causes impaired Venous NVD
autoregulation of retinal blood flow, accumulation of dilation
advanced glycosylation end products, and accumulation
of retinal cell sorbitol. Normally, retinal blood flow is Hard
tightly autoregulated. For example, retinal blood flow exudates
does not change in normal individuals unless the mean
arterial blood pressure is raised more than 40%. Hyper-
glycemia impairs this autoregulation, and retinal blood
flow increases lead to increased shear stress, vascular
leakage, and extracellular fluid accumulation. Retinal
pericytes and microvascular cells become damaged and
dysfunctional. Microaneurysms are saccular outpouch-
ings that appear in retinal vessels at sites of retinal peri-
cyte loss. Microthrombosis and occlusion of retinal
capillaries lead to retinal ischemia and capillary leakage.
Retinal ischemia triggers the release of vascular growth
factors (e.g., vascular endothelial growth factor, plate-
let-derived growth factor, fibroblast growth factor,
erythropoietin, and insulinlike growth factor 1). These
growth factors promote the development of new blood
vessels (neovascularization) in an attempt to revascular-
ize ischemic retina. The two major forms of diabetic
retinopathy are nonproliferative and proliferative.

NONPROLIFERATIVE DIABETIC Dot and blot
RETINOPATHY hemorrhages

Nonproliferative diabetic retinopathy (NPDR) is asso- Preretinal Cotton wool patches
ciated with the findings of microvascular abnormalities
(e.g., dilated retinal veins, occluded vessels with result- hemorrhage
ant dot-and-blot hemorrhages, and microaneurysms), Neovascularization of
nerve fiber layer retinal infarcts (cotton-wool patches),
intraretinal hemorrhages, macular edema, and hard Narrowed arteriole optic disc (NVD)
exudates (leakage of lipid and proteinaceous material).
The macular edema in patients with NPDR is respon- NVE
sible for vision loss. The severity of NPDR predicts the
risk of progressing to proliferative retinopathy. For factors triggers the development of new vessels from and leakage from sites of neovascularization. Neovas-
example, although the 1-year risk of progression to adjacent retinal vessels. The intraluminal proliferation cularization at the disc (NVD) refers to neovasculari-
proliferative retinopathy for patients with mild NPDR of cells results in vascular occlusion and rupture, result- zation occurring at or within 1500 μm (or ≤1 disc
is 5%, the risk is 75% for those with very severe NPDR. ing in the appearance of flame-shaped (occur in inner diameter [DD]) of the optic disc. Neovascularization
retina closer to the vitreous) and dot-and-blot hemor- elsewhere (NVE) refers to neovascularization that is
PROLIFERATIVE DIABETIC RETINOPATHY rhages (occur deeper in the retina) proximal to the located more than 1500 μm (or >1 DD) away from the
occlusion and intraretinal infarcts (cotton-wool patches) optic disc.
Proliferative diabetic retinopathy (PDR) is distin- distal to the occlusion. In the early stages of PDR, the
guished from NPDR by the presence of neovasculariza- new vessels can be seen as fine loops, and existing veins MACULAR EDEMA
tion that arises from retinal vessels or the optic disc. may become tortuous and beaded and develop loops.
The neovascularization leads to acute vision loss caused As PDR progresses, there is marked neovascularization Macular edema is retinal thickening and edema involv-
by hemorrhage (preretinal and vitreous), fibrosis, and covering more than 50% of the optic disc and an ing the macula, and it may complicate PDR or NPDR.
traction retinal detachment (see Plate 5-14). PDR increased risk for preretinal and vitreous hemorrhage. Macular edema is the most common cause of vision loss
usually arises from a background of NPDR. Arteriolar If severe PDR is not treated, there is a 60% risk of from diabetes and can be diagnosed by stereoscopic
narrowing is usually evident on the fundus examination. progression to vision loss over 5 years. The findings of fundus examination or fluorescein angiography. It is
The ischemia-induced release of vascular growth PDR are evident on the fundus examination. Intrave- termed clinically significant macular edema when the
nously administered fluorescein dye (fluorescein angi- thickening in the macular region is of sufficient extent
ography) can assess areas of capillary under perfusion and location to threaten central visual function.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 141

Plate 5-14 Endocrine System

COMPLICATIONS OF
PROLIFERATIVE DIABETIC
RETINOPATHY

Proliferative diabetic retinopathy (PDR) is associated Fibrovascular proliferation Interaction between
with neovascularization that arises from retinal vessels on optic disc and on vessels hematogenous iron
or the optic disc. As PDR progresses, the marked neo- and vitreous accelerates
vascularization increases the risk for preretinal and vit- shrinkage and traction
reous hemorrhage. Severe PDR leads to acute vision
loss caused by hemorrhage (preretinal and vitreous), Vitreoretinal
fibrosis, and traction retinal detachment. If severe PDR traction
is not treated, there is a 60% risk of progression to
vision loss over 5 years. Puberty and pregnancy can Vitreous hemorrhage
accelerate retinopathy progression.
Fibrovascular proliferation
Diabetic retinopathy (DR) is usually asymptomatic and vitreous contraction
until the late stages. Symptoms include decreased visual cause traction retinal
acuity related to macular edema, a “curtain falling” sen- detachment
sation with a vitreous hemorrhage, and floaters during
the resolution phase of vitreous bleeds. Eye-directed Vitreous
therapy decreases the rate of disease progression. Thus, contraction
annual screening for DR is important so that preventa-
tive therapy can be instituted. A comprehensive eye Traction retinal
examination with slit-lamp biomicroscopy combined detachment
with indirect ophthalmoscopy on dilated fundi by an
experienced ophthalmologist and seven-field digital microvascular lesions around hard exudates, avoiding Vitreal contraction also predisposes to traction
stereoscopic retinal photography are standard screen- the fovea region. retinal detachment, which leads to vision loss when the
ing methods. Eye examinations should be done more fovea or the macula is involved. Surgical vitrectomy can
frequently during pregnancy. Vitreous hemorrhage results from rupture of fragile relieve vitreous traction.
new vessels or from contraction of the fibrovascular
The newly recruited vessels of neovascularization proliferation that causes avulsion of retinal vessels. Pharmacologic approaches for treating PDR are
initially grow along the plane of the retina. However, Whereas blood that collects behind the detached pos- under investigation. Candidate agents include intra-
as the vitreous gradually pulls away and detaches from terior vitreous face is absorbed over many weeks, blood vitreal administration of vascular endothelial growth
the retina, the new vessels extend into the vitreous in the vitreous itself can turn white and is absorbed factor inhibitors.
cavity. These aberrant vessels are fragile and at high risk much more slowly. This opaque vitreous humor can be
for rupture with resultant vitreous hemorrhage. The surgically removed.
neovascularization process can also lead to a fibrovas-
cular proliferation that can distort the retina and pre-
dispose to retinal detachment.

Before the advent of tight glycemic control, studies
showed that the prevalence of DR increased progres-
sively in patients with increasing duration of diabetes;
DR would start within 3 to 5 years of the diagnosis of
type 1 diabetes. Subsequent studies documented that
improved glycemic control dramatically decreased the
development and progression of DR. Thus, the first
steps in treatment should be to prevent the develop-
ment of DR or to prevent progression of existing DR
by maximizing efforts at good glycemic control. In
addition, if hypertension is present, treatment should
be targeted for average blood pressure less than
130/80 mm Hg.

In patients with established PDR, the treatment goals
are to preserve vision, repair high-risk lesions, and
reduce the rate of progression. Panretinal (scatter) laser
photocoagulation is the primary treatment for patients
with severe PDR. Administering approximately 1200 to
1800 laser burns (in grid that targets peripheral retinal
tissue and avoids large vessels and the optic disc) per
eye over two to three sessions decreases the risk of
severe vision loss by 50%. Panretinal laser treatment
decreases viable hypoxic growth factor–generating
cells, increases oxygen delivery to the inner retina, and
increases relative perfusion to viable retina.

Focal laser photocoagulation is the optimal treat-
ment for clinically significant macular edema. Laser
treatment is directed at microaneurysms and the

142 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-15 Pancreas

DIABETIC NEPHROPATHY GLOMERULOSCLEROSIS

Diffuse glomerulosclerosis

Diabetic nephropathy is a major cause of morbidity and Edema
mortality in patients with type 1 or type 2 diabetes mel-
litus. Diabetic nephropathy is characterized as the triad May cause
of proteinuria, hypertension, and renal impairment. nephrotic
Approximately 40% of patients with type 1 diabetes and syndrome
20% of patients with type 2 diabetes develop some and/or renal
degree of diabetic nephropathy. Diabetes is the single failure, with
most common cause of end-stage renal disease (ESRD). or without
hypertension
Diabetic nephropathy can be considered in five
stages or phases. The initial phase of diabetic nephropa- Albuminuria
thy is hyperfiltration with increased capillary glomeru-
lar pressure and elevated glomerular filtration rate Waxy casts
(GFR) (e.g., >150 mL/min). The glomerular hyperfil-
tration is associated with glomerular hypertrophy and Nodular glomerulosclerosis
increased renal size. The second stage is termed the
silent stage. In this stage, although the GFR is normal This nodular component
and there is no proteinuria, glomerular basement mem- (Kimmelstiel-Wilson nodules)
brane thickening and mesangial expansion are occur- associated with hyaline deposits
ring. The third stage is termed incipient nephropathy, in the glomerular arterioles is
during which the urinary albumin excretion rate pathognomonic for diabetic
becomes abnormal (e.g., 30–300 mg/24 hr). Also at nephropathy
this stage, systemic hypertension may become evident.
The fourth stage of diabetic nephropathy is the overt antiinflammatory drugs and cyclo-oxygenase-2 inhibi- than 3.5 g/1.73 m2 per 24 hours, hypoalbuminemia
nephropathy or macroalbuminuria stage. In this stage, the tors should be avoided because of their adverse impact (serum albumin concentration <3 g/dL), and peripheral
24-hour urinary albumin excretion is more than on hypertension. In addition, radiographic contrast dye edema. Microscopic examination of the urine sediment
300 mg, and creatinine levels in the blood rise. The should be avoided because of its adverse impact on renal may show waxy casts (degenerated cellular casts of col-
majority of patients at this stage have systemic hyper- function and risk for acute renal failure. lecting tubules), which are found in patients with severe
tension. Untreated hypertension can accelerate the chronic renal disease. For patients who progress to
decline in GFR, which in turn accelerates systemic Progressive diabetic nephropathy may result in ESRD, renal replacement options include hemodialysis,
hypertension. The fifth and final stage is uremia, the severe proteinuria and associated symptoms that peritoneal dialysis, renal transplantation, and combined
effective treatment of which requires renal replacement are referred to as the nephrotic syndrome. Nephrotic syn- pancreas–kidney transplantation.
therapy. drome is defined by urinary protein excretion of more

As with diabetic retinopathy, the pathogenesis of
diabetic nephropathy is complex and related to a
hyperglycemia-triggered cascade of mechanisms.
Chronic hyperglycemia causes impaired autoregulation
of renal blood flow with intraglomerular hypertension,
accumulation of advanced glycosylation end products,
generation of mitochondrial reactive oxygen species,
activation of protein kinase C, and accumulation of
sorbitol. Improved glycemic control in patients with
diabetes can slow the development of nephropathy.

Glomerular basement membrane thickening and
mesangial expansion are prominent glomerular
abnormalities in diabetes that progress to nodular
(Kimmelstiel-Wilson lesion) or diffuse glomeruloscle-
rosis. Nodular glomerulosclerosis is associated with
hyaline deposits in the glomerular arterioles. A diabetic
tubulopathy can also develop and may result in a type
IV renal tubular acidosis with hyperkalemia and hyper-
chloremic metabolic acidosis, an outcome associated
with hyporeninemic hypoaldosteronism.

The cornerstones of treatment for diabetic neph-
ropathy are optimizing glycemic control and hyperten-
sion management. Decreases in glycosylated hemoglobin
are associated with a decreased risk of development of
microalbuminuria and decreased rate of progression
through the stages of diabetic nephropathy. Angioten-
sion-converting enzyme (ACE) inhibitors and angi-
otensin receptor blockers (ARBs) are the antihypertensive
drug classes of choice because these agents appear to
have renoprotective effects that exceed their antihy-
pertensive effects. ACE inhibitors and ARBs decrease
urinary albumin excretion by more than 30% and
retard the progression from microalbuminuria to
overt proteinuria. In addition, exposure to agents
that have adverse effects on blood pressure or renal
function should be avoided. For example, nonsteroidal

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 143

Plate 5-16 Endocrine System

DIABETIC NEUROPATHY

Approximately 50% of those with diabetes of more than Wrist drop Ankle drop Loss of
25 years’ duration develop symptomatic diabetic neu- vibration
ropathy. Diabetic neuropathy is not a single disorder, sense
but rather multiple disorders depending on the types
of nerve fibers involved.

FOCAL NEUROPATHIES Paresthesia, hyperalgesia, or hypesthesia Third cranial nerve palsy presents
with diplopia. Examination reveals
In general, mononeuropathies occur in older patients Pupillary abnormalities ptosis and ophthalmoplegia
with diabetes. Mononeuropathies are a result of vascular
obstruction and are typically acute in onset, associated Orthostatic
with pain and motor weakness, and self-limited (most hypotension
resolve over 2 months). Nerves that are commonly and nocturnal
involved include cranial nerves III, VI, and VII; the hypertension
ulnar nerve; and the peroneal nerve. Patients may
present with wrist drop or ankle drop. With third cranial Polyradiculopathy
nerve involvement, patients complain of diplopia, and Nocturnal diarrhea
examination shows ptosis and ophthalmoplegia. Dia- Neurogenic bladder
betic polyradiculopathy is characterized by severe pain Impotence
in the distribution of one or more nerve roots and may
be accompanied by motor weakness. For example, inter- Autonomic neuropathy Neuropathic (painless) ulcer
costal or truncal radiculopathy presents with pain over
the thorax or abdomen. Diabetic polyradiculopathy is Large-fiber neuropathies involve the myelinated AUTONOMIC NEUROPATHY
usually self-limited and resolves over 1 year. and rapidly conducting sensory or motor nerves that
are normally responsible for vibration perception, cold Dysfunction of the sympathetic and parasympathetic
PROXIMAL MOTOR NEUROPATHIES thermal perception, position sense, and motor function. nervous systems has the potential to cause malfunction
Typical initial symptoms include a sensation of walking of almost all body systems. Examples of organ systems
Proximal motor neuropathies (also known as diabetic on pebbles or cotton, inability to discriminate among that may be affected by autonomic neuropathy include
amyotrophy, proximal neuropathy, femoral neuropa- coins, and trouble turning pages of a book. Large-fiber pupillary abnormalities with Argyll-Robertson-type
thy, diabetic neuropathic cachexia, and Ellenberg neuropathies are easily detected on physical examina- pupil and decreased diameter of dark-adapted pupil;
cachexia) affect primarily older patients with type 2 tion (e.g., loss of vibration sense, loss of proprioception, cardiovascular system with orthostatic hypotension,
diabetes. Symptoms usually start with thigh and pelvic loss of deep tendon reflexes). There may be wasting of nocturnal hypertension, resting tachycardia, silent
girdle pains that progress to marked atrophy of the the small muscles in the feet and hands. myocardial infarction, and heat and exercise intoler-
quadriceps muscles. Patients present with symptoms ance; genitourinary system with erectile dysfunction,
caused by lower extremity proximal muscle weakness Usually DSPN presents with signs and symptoms of retrograde ejaculation, and neurogenic bladder with
(e.g., must use arms to assist them when rising from a both small- and large-fiber nerve damage. The longer urinary retention; gastrointestinal system with gas-
chair). The signs and symptoms may start unilaterally nerves are especially vulnerable, and most patients troparesis, constipation, nocturnal diarrhea, and fecal
but usually progress to bilateral involvement. Pain may have a stocking-and-glove type sensory loss that may incontinence; sweating disturbances with gustatory
be a predominant component of the clinical presenta- spread proximally. Neuropathic foot ulcers and Char- sweating, hyperhidrosis, and anhidrosis; and blunted
tion, and profound weight loss and depression are cot’s arthropathy (neurogenic arthropathy) can result adrenomedullary response to hypoglycemia, leading to
common. Axonal loss is the primary pathophysiologic from loss of proprioception, pain, and temperature per- hypoglycemic unawareness.
process, and electromyography shows lumbosacral ceptions (see Plate 5-18).
plexopathy. Most of these patients prove to have
chronic inflammatory demyelinating polyneuropathy,
monoclonal gammopathy, ganglioside antibody syn-
drome, or an inflammatory vasculitis.

DISTAL SYMMETRIC POLYNEUROPATHY

Distal symmetric polyneuropathy (DSPN) is the most
common form of diabetic neuropathy. The onset of
DSPN is usually slow and involves small and/or large
fibers of either sensory and/or motor nerves. Small fiber
neuropathy usually manifests as paresthesia, hyperalge-
sia (increased pain response to a normally painful stim-
ulus), allodynia (pain response from a stimulus that is
not normally painful), or hypesthesia involving the feet
and lower extremities. The pain is usually described as
burning. The paresthesias are described as pins and
needles, numbness, tingling, cold, or burning. Physical
examination usually reveals reduced pinprick and light
tough sensations and loss of thermal sensitivity. An
acute painful small fiber neuropathy may develop with
the initiation of therapy to improve glycemic control.

144 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-17 Pancreas

ATHEROSCLEROSIS IN DIABETES

The type of macrovascular disease in patients with dia- Intimal proliferation (atherosclerosis);
betes mellitus is similar to that in individuals without lumen greatly reduced
diabetes. However, the vascular disease is more exten-
sive and rapidly progressive in the setting of diabetes, Medial calcification (Mönckeberg type of sclerosis)
even when adjustments are made for other risk factors plus some intimal thickening and thrombosis
that are more prevalent in people with diabetes (e.g.,
hypertension and dyslipidemia). Glycosylated hemo-
globin has been shown to be an independent risk factor
for macrovascular disease. Thus, diabetes should be
considered a coronary heart disease (CHD) risk equiva-
lent when assessing cardiovascular risk and designing
treatment programs for hyperlipidemia (see Plate 7-5).

After adjusting for all known cardiovascular risk
factors, insulin resistance is an independent risk factor
for macrovascular disease. Insulin resistance at the adi-
pocyte leads to increased free fatty acid release that
stimulates hepatic very low-density lipoprotein (VLDL)
secretion, which in turn leads to proatherogenic dysli-
pidemia, defined as low serum concentration of high-
density lipoprotein (HDL) cholesterol, high serum
concentration of VLDL, and high serum concentration
of small dense low-density lipoprotein (LDL) choles-
terol. Small dense LDL cholesterol is more efficient at
penetrating the blood vessel wall to prompt the athero-
genic process (see Plates 7-12 and 7-13).

Insulin itself has proatherogenic properties. Insulin
and hyperglycemia potentiate the effects of platelet-
derived growth factor on vascular smooth muscle cell
proliferation. Insulin also stimulates vascular smooth
muscle cells to produce plasminogen activator inhibitor
1. Hyperglycemia inhibits endothelial cell nitric oxide
production and potentiates collagen-induced platelet
activation.

Mönckeberg arteriosclerosis (medial calcific sclero-
sis) is a form of arteriosclerosis that is more common
in patients with diabetes. In advanced cases, the arteries
become rigid and lose their distensibility and are
referred to as pipestem arteries. The calcification may be
evident on plain radiographs.

CARDIOVASCULAR RISK REDUCTION CT angiogram of the abdominal aorta Aortogram showing advanced atheromatous disease
shows the infrarenal abdominal aorta involving the infrarenal abdominal aorta with multiple
Traditional CHD risk factors (dyslipidemia, obesity, is mildly ectatic. There is a stenosis at areas of ulceration. Tight atheromatous stenosis
hypertension, insulin resistance) are commonly present the origin of the left internal iliac artery. involving the origin of the right common iliac artery.
in individuals with type 2 diabetes. Thus, the athero-
sclerosis risk in individuals with diabetes is multifacto- hospital admission are independently correlated with Cardioselective β-adrenergic inhibitors are routinely
rial and likely synergistic. Intensive long-term treatment both early and late mortality after an MI. Optimizing given to patients with diabetes in the setting of acute
of these associated risk factors lowers the risk of glycemic control can improve myocardial cell metabo- coronary syndromes to decrease mortality rates. The
macrovascular events by at least 50%. Lowering lism by shifting from free fatty acid oxidation to glucose β-adrenergic inhibitors likely decrease the unrestrained
serum LDL cholesterol concentrations (even when oxidation for generation of adenosine triphosphate. sympathetic nervous system overactivity related to
pretreatment levels are in the reference range) with Treatment with an angiotensin-converting enzyme autonomic neuropathy. Aspirin has been shown to
hydroxymethylglutaryl coenzyme A reductase inhibi- inhibitor also decreases mortality in patients with lower the risk of MI in individuals with diabetes. Thus,
tors (statins) reduces cardiovascular events in patients diabetes after an MI. The mechanisms of this benefit aspirin (81–325 mg/d) is indicated for both primary and
with diabetes. Thus, lipid-directed pharmacologic are likely related to limitation of infarct size and secondary macrovascular event protection in all patients
therapy is a key intervention along with lifestyle modi- improving endothelial cell function and fibrinolysis. with diabetes.
fication (weight reduction, regular isotonic exercise,
and smoking cessation), optimizing glycemic control,
treatment of hypertension, and aspirin therapy.

The fatality rate with myocardial infarction (MI) is
twice as high in patients with diabetes than in nondia-
betic patients. This increased risk is likely related to
multiple factors (e.g., more severe underlying CHD,
early reinfarction caused by impaired fibrinolysis, auto-
nomic neuropathy predisposing to a sympathovagal
imbalance, or maladaptive remodeling of the left ven-
tricle). Blood glucose concentrations at the time of

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 145

Plate 5-18 Endocrine System

VASCULAR INSUFFICIENCY IN
DIABETES: THE DIABETIC FOOT

Diabetic foot ulcers occur in approximately 10% of Dependent rubor, absence Grade I: superficial full-thickness ulcer
patients with type 1 or type 2 diabetes mellitus. Approx- of dorsalis pedis pulsation
imately 1% of patients with diabetes require an amputa- Ulcer with lymphedema
tion, a last-resort surgical step that is usually preceded Grade IV: partial gangrene is indicated with a combination of plain radiographs,
by foot ulcers. Diabetes is the most common non- magnetic resonance imaging, and bone scintigraphy.
trauma cause of lower limb amputation. Diabetic foot Grade V: gangrene of the whole foot The treatment of osteomyelitis requires systemic anti-
ulcers are more common in patients who also have Grade 4: Partial gangrene (e.g., toes and forefoot) biotic therapy and, in many cases, surgical removal
other evidence of other micro- or macrovascular disease Grade 5: Gangrene of the whole foot of infected bone. Localized gangrene of a toe that is
(retinopathy, nephropathy, or coronary heart disease). Key steps to ensure effective healing of diabetic foot not associated with infection may be allowed to self-
amputate. However, more extensive gangrene is a
Diabetic neuropathy (see Plate 5-16) plays a key role ulcers include confirming adequate arterial blood flow, medical urgency that requires hospitalization, treat-
in diabetic foot ulcers. For example, sympathetic auto- treating underlying infection, removing pressure from ment of the underlying infection, optimizing glycemic
nomic neuropathy may result in dry skin (from the wound and surrounding area, and debriding all dead control, vascular assessment, and consultation with vas-
decreased sweat production), leading to scaling, cracks, and macerated tissue. Pressure relief can usually be cular and orthopedic surgeons.
and fissures, which provide a portal for infection. Motor achieved with a removable cast boot. A nonhealing
neuropathy affects the small intrinsic muscles of the foot ulcer should be investigated for ischemia with
feet so that the larger muscles in the anterior tibial noninvasive techniques and arteriography in some
compartment are unopposed, causing subluxation of cases. If osteomyelitis is suspected, additional imaging
the proximal interphalangeal-metatarsal joints (claw toe
deformity). The prominent metatarsal heads become
the point of impact of body weight and friction and a
common site of diabetic foot ulcer development. Dia-
betic neuropathy–induced proprioceptive loss decreases
the patient’s recognition of these sites of irritation and
inflammation. Plantar callus, which predisposes to
ulceration, may build up at these high pressure sites.
The presence of neuropathy increases the risk of dia-
betic ulcer formation sevenfold.

Patients with diabetes should have annual compre-
hensive foot examinations to assess for evidence of neu-
ropathic or vascular deficits, deformity, callus formation,
or dry skin. Vibration sensation should be tested with
a 128-Hz tuning fork at the great toe. Pressure sensa-
tion should be tested with a Semmes-Weinstein 5.07
(10-g) monofilament applied to buckling pressure on
the plantar surface of the foot. In addition, the Achilles
tendon reflex and temperature sensation should be
checked. Vascular insufficiency can be evaluated with
assessment of pulses (dorsal pedis, posterior tibial), skin
temperature, presence of hair on skin, color of skin, and
assessment for dependent rubor. Dependent rubor is
present when the skin and nail beds are dark red because
of the inadequate arterial flow and the presence of
venous blood containing reduced hemoglobin in dilated
venous capillaries; when the foot is raised above the
level of the heart, the venous blood drains away and
unmasks the pallid tissues supplied by insufficient arte-
rial flow. Patients who are determined to have risk
factors for foot ulcer formation should be advised by a
foot care team that includes diabetes physician special-
ists, diabetes nurse educators, podiatrists, orthotic spe-
cialists, orthopedic surgeons, and vascular surgeons.
Prophylactic measures to prevent diabetic foot ulcers
include smoking cessation; avoiding walking barefoot;
checking water temperature before stepping into a
bath; keeping the toenails trimmed; inspecting the feet
daily for blisters, swelling, or redness; and wearing
properly fitting shoes.

The Wagner diabetic foot ulcer classification scheme
is as follows:

Grade 0: No ulcer but high-risk (e.g., deformity,
callus, insensitivity)

Grade 1: Superficial full-thickness ulcer
Grade 2: Deeper ulcer that penetrates tendons but

does not involve bone
Grade 3: Deeper ulcer with bone involvement

(osteitis)

146 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-19 Pancreas

DIABETES MELLITUS IN Relevant Human Blood pressure

PREGNANCY pathophysiology chorionic

Diabetes mellitus is the most common medical compli- In the 1st trimester somatomammotropin
cation of pregnancy. Gestational diabetes mellitus of pregnancy, Lipolysis (hCS)
(GDM) complicates 4% of pregnancies, and preexisting
type 1 or type 2 diabetes mellitus (pregestational diabe- increasing estrogen Glucose uptake
tes) complicates 0.5% of all pregnancies. Diabetes in and progesterone
pregnancy is associated with unique risks for the fetus
and the mother. Poorly controlled diabetes is associated are associated with
with high risks for spontaneous abortion, major con-
genital malformations, premature birth, preeclampsia, a decrease in fasting
and stillbirths. Although maternal glucose crosses the
placenta, insulin does not, resulting in increased fetal plasma glucose
pancreas production of insulin, which leads to increased
fetal somatic growth. concentrations

Fetal macrosomia (fetal birth weight >4500 g) can Plasma glucose Estrogen
complicate delivery and predispose to birth trauma. To concentrations rise Progesterone
prevent these risks, pregestational diabetes should be in the 2nd and 3rd
under optimal glycemic control for months before con- trimesters because
ception and throughout pregnancy. In addition, all of increasing levels
pregnant women should be tested for GDM and treated of hCS
when identified.
Maternal complications
In the first trimester of pregnancy, the increasing Ketoacidosis, glycosuria,
blood concentrations of estrogen and progesterone are hyperglycemia, preterm labor,
associated with a decrease in fasting plasma glucose
concentrations by an average of 15 mg/dL. Plasma BP, UTI, uterine atony,
glucose concentrations rise in the second and third tri- polyhydramnios, retinopathy
mesters of pregnancy, primarily because of increasing
circulating levels of human chorionic somatomammo- Fetal complications
tropin (hCS), also called human placental lactogen. The Spontaneous abortion, fetal demise,
structure of hCS is very similar to that of human growth cardiac defects, neural tube defects,
hormone and has most of the actions of growth limb defects, hypocalcemia, hypoglyc-
hormone; hCS enhances lipolysis and decreases glucose emia, macrosomia, hyperbilirubinemia,
utilization. polycythemia, prematurity,
respiratory distress syndrome
The diagnostic criteria for pregestational type 1 or
type 2 diabetes are as outlined in Plates 5-11 and 5-12. Urinary glucose useless to Physiologic
GDM is defined as hyperglycemia or glucose intoler- screen or monitor diabetes glycosuria
ance with an onset or first recognition during preg- during pregnancy
nancy. All women without known diabetes should be
tested for GDM between weeks 24 and 28 of gestation. Screening for gestational diabetes
Testing for GDM should be done earlier in pregnancy accomplished via measurement
if risk factors are present (pre-pregnancy body mass of serum glucose after challenge
index >30 kg/m2, history of GDM, prior infant with a followed by 3-hour glucose
major congenital malformation, or family history of tolerance test for those with
diabetes in a first-degree relative). The initial screening positive test results
test is a 50-g oral glucose challenge test (GCT) with
measurement of plasma glucose 1 hour later. Glucose Diabetes is monitored by
levels above 130 mg/dL should trigger confirmatory using a glucose reflectance meter
testing with a 3-hour 100-g oral glucose tolerance test
(OGTT). If the 1-hour GCT glucose is more than with
180 mg/dL and fasting plasma glucose is more than
95 mg/dL, then GDM is confirmed, and a 3-hour E. Hatton
OGTT is not needed. In addition, GDM is confirmed
on the 3-hour OGTT if two or more of the following Management objectives involve efforts to return glucose levels to as close to normal as possible
plasma glucose concentrations are exceeded: fasting through a combination of diet, exercise, insulin (as indicated), and tight control in patients
above 95 gm/dL, 1 hour above 180 mg/dL, 2 hours with pregestational diabetes
above 155 mg/dL, or 3 hours above 140 mg/dL.
blood glucose self-monitoring. Fetal growth and devel- pregnancies. In addition, women who are diagnosed
Patients with GDM should be treated with daily exer- opment should be monitored by ultrasonography. with GDM are at a 50% risk of developing permanent
cise, diet (with relative carbohydrate restriction [33%– diabetes over the subsequent 10 years.
40% of calories] and guidance on caloric allotment and Diabetes comorbidities, including hypertension
calorie distribution), and pharmacologic therapy if (increased blood pressure [BP]), retinopathy in patients There are also long-term effects on children whose
needed. Patients should do self-monitoring of blood with pregestational diabetes, ketoacidosis, and urinary mothers had diabetes in pregnancy. The in utero expo-
glucose at least four times daily (fasting and 1 to 2 hours tract infections (UTIs), should be monitored and sure to maternal hyperglycemia promotes fetal hyper-
postprandial). Target glucose levels during pregnancy treated during pregnancy as indicated. insulinemia and an increase in fetal fat cells, changes
are 70 to 95 mg/dL fasting and less than 120 mg/dL at that have been linked to obesity and insulin resistance
1 to 2 hours after a meal. Insulin treatment is needed In most women with GDM, the blood glucose con- in children and impaired glucose tolerance and diabetes
in about 15% of women with GDM because they cannot centrations return to normal postpartum; however, in adults.
achieve these glycemic targets with diet and exercise. there is a 60% risk of recurrent GDM with future
Insulin doses should be titrated based on findings on

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Plate 5-20 Endocrine System

TREATMENT OF TYPE 2 Liver MATCHING PHARMACOLOGY TO PATHOPHYSIOLOGY
DIABETES MELLITUS Pancreas

Improved glycemic control in individuals with type 2 Therapy: Therapy:
diabetes mellitus is associated with decreased rates of Biguanides Sulfonylureas
microvascular complications (retinopathy, nephropa- Thiazolidinediones Insulin
thy, and neuropathy). The treatment goal should be to Amylin analogs Repaglinide
maintain the hemoglobin A1c (HbA1c) at a level less than Nateglinide
7%, recognizing that HbA1c values in the normal range Increased Insulin analogs
(<6%) are optimal. Additional glycemic targets include glucose Incretin-related agents
fasting and premeal plasma glucose of 70 to 130 mg/dL production
and 2-hour postprandial glucose of less than 180 mg/dL. Decreased
insulin
NONPHARMACOLOGIC THERAPY secretion

The key to successful implementation of lifestyle Hyperglycemia
interventions is comprehensive diabetes education with
emphasis on self-management. Interventions include Increased Adipose tissue Decreased
dietary modification based on nutrition counseling, glucose Muscle peripheral
regular isotonic exercise, weight reduction, behavior absorption glucose
modification, and self-monitoring of blood glucose uptake
(SMBG). Exercise improves glycemic control, insulin Intestine
sensitivity, and cardiovascular fitness. The frequency Therapy:
and timing of SMBG depend on the type of pharmaco- Therapy: Physical activity
logic therapy. Nutrition Thiazolidinediones
␣-glucosidase inhibitors
PHARMACOTHERAPY Incretin-related agents
Amylin analogs
Pharmacotherapeutic options for the management of
type 2 diabetes include seven broad classes of drugs that nateglinide are administered with each meal. Insulin Amylin Analogues
are targeted at different pathophysiologic mechanisms secretagogues can cause hypoglycemia.
that contribute to hyperglycemia. Amylin is cosecreted with insulin by the β-cell and has
Agents that Slow Enteric Carbohydrate complementary actions to insulin by delaying gastric
Insulin Sensitizers with Primary Action Absorption—α-Glucosidase Inhibitors emptying, reducing appetite, and suppressing glucagon
in the Liver—Biguanides secretion. Pramlintide is an amylin analogue that is
α-glucosidase inhibitors (AGIs) (acarbose, miglitol) administered subcutaneously at each meal.
Metformin, the only biguanide currently available in the inhibit the terminal step of carbohydrate digestion at
United States, activates the adenosine monophosphate– the intestinal epithelium and delaying carbohydrate Insulin
activated protein kinase. Metformin reduces hepatic absorption. They must be administered at the begin-
insulin resistance, resulting in decreased hepatic gluco- ning of each meal. The main side effects are flatulence Subcutaneous administration of insulin serves to
neogenesis. There is no risk for hypoglycemia, and this and diarrhea. supplement endogenous insulin production. The
agent should be considered in all patients with type 2 types of insulin include rapid-acting insulin analogues
diabetes. The main side effect is gastrointestinal intoler- Incretin-Related Agents (lispro, aspart, glulisine), short-acting analogues
ance. Because of the risk of lactic acidosis, metformin (regular insulin), intermediate-acting analogues (neutral
should not be used in patients with renal insufficiency. The finding that orally administered glucose has a protamine Hagedorn [NPH]), and long-acting ana-
greater stimulatory effect on insulin secretion than logues (glargine, detemir). Side effects include hypogly-
Insulin Sensitizers with Primary intravenously administered glucose is called the incretin cemia and weight gain.
Action on Peripheral effect. Glucagon-like peptide 1 (GLP-1) and gastric
Tissues—Thiazolidinediones inhibitory peptide (GIP) mediate the incretin effect. INITIAL APPROACH TO MEDICAL
GLP-1 stimulates insulin secretion, slows gastric emp- MANAGEMENT
Pioglitazone and rosiglitazone, the two thiazolidi- tying, and reduces appetite. GLP-1 has a short plasma
nediones (TZDs) currently available, modulate perox- half-life because of rapid degradation by dipeptidyl In general, metformin along with diet and exercise
isome proliferator-activated receptors (PPARs). TZDs peptidase IV (DPP-IV). Exenatide is an incretin should be the initial therapy for patients with type 2
decrease peripheral insulin resistance and lower serum mimetic that is structurally similar to GLP-1. It is diabetes. For patients with newly diagnosed diabetes
triglyceride levels. The main side effects are weight gain administered subcutaneously twice daily and is resistant who have fasting glucose concentration more than
caused by subcutaneous fat accumulation and fluid to DPP-IV degradation. Nausea is the most common 250 mg/dL, more than one pharmacologic agent is
retention. side effect. Liraglutide is a DPP-IV-resistant GLP-1 usually needed (e.g., metformin and a sulfonylurea or
analogue that is administered subcutaneously once insulin). For established patients with suboptimal glyc-
Insulin Secretagogues—Sulfonylurea daily. Sitagliptin, saxagliptin, and vildagliptin are orally emic control because of postprandial hyperglycemia,
Receptor Agonists administered DPP-IV inhibitors that result in mild the addition of AGIs, rapid-acting insulin, or exenatide
increases in endogenous GLP-1 and GIP. should be considered.
The sulfonylurea receptor (SUR2) is a subunit of the
adenosine triphosphate–sensitive potassium channel on
the plasma membrane of the β-cell, where it functions
as a glucose sensor to trigger insulin secretion. Sulfo-
nylureas include first-generation agents (acetohe-
xamide, chlorpropamide, tolazamide, and tolbutamide)
and second-generation agents (glipizide, glyburide,
and glimepiride). Long-acting forms of sulfonylureas
facilitate once-daily dosing. Repaglinide and nategli-
nide are agents in the meglitinide family of insulin
secretagogues, which activate a distinct SUR1 binding
site. Because of their short half-lives, repaglinide and

148 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-21 Pancreas

TREATMENT OF TYPE 1
DIABETES MELLITUS

It has been clearly demonstrated that optimizing glyc- Intensive insulin therapy should be
emic control with intensive insulin therapy in patients started as soon as possible after the
with type 1 diabetes mellitus leads to clinically signifi- diagnosis of type 1 diabetes mellitus
cant decreased risks for retinopathy, nephropathy, neu-
ropathy, and cardiovascular disease. The treatment goal The MDI and CSII methods to deliver
should be to maintain the hemoglobin A1c (HbA1c) at a insulin are designed to replicate
level less than 7%, recognizing that HbA1c values in the normal physiology
normal range (<6%) are optimal. Additional glycemic
targets include fasting and premeal plasma glucose at CSII and MDI require self-monitoring
70 to 130 mg/dL and 2-hour postprandial glucose less of blood glucose and then adjusting
than 180 mg/dL. Two methods of insulin delivery that and/or supplementing the pre-meal
can be used to achieve this glycemic targets are continu- insulin doses
ous subcutaneous insulin infusion (CSII; insulin pump)
and multiple daily injections (MDIs) of insulin.

The types of insulin currently available include
rapid-acting insulin analogues (lispro, aspart, glulisine)
with an onset of action at 15 minutes and peak effect at
1 hour; short-acting (regular insulin) analogues with an
onset of action at 30 to 60 minutes and peak effect at 2
to 4 hours; intermediate-acting analogues (neutral pro-
tamine Hagedorn [NPH]) with an onset of action at 1
to 3 hours and a peak effect at 6 to 8 hours; and long-
acting analogues (glargine, detemir) with an onset of
action at 1 hour, peak effect at 9 or more hours, and
duration of effect for 24 hours.

MONOMERIC INSULIN ANALOGUES

Modifications of the human insulin molecule can
change its kinetics. For example, rapid-acting insulin
analogues are made with recombinant DNA technology
by modifying insulin structure to decrease the ability of
insulin to self-aggregate after subcutaneous injection,
leading to rapid absorption and action. Insulin lispro is
synthesized by reversing the amino acids at positions 28
and 29 in the β-chain of human insulin (lysine at β-28
and proline at β-29). Aspartic acid is substituted for
proline at β-28 to form insulin aspart. Insulin glulisine
is produced by substituting lysine for asparagine at β-3
and substituting glutamic acid for lysine at β-29.

LONG-ACTING INSULIN ANALOGUES CONTINUOUS SUBCUTANEOUS INSULIN mechanical pump continuously administers rapid-
INFUSION AND MULTIPLE DAILY acting insulin analogues through a catheter that is
Insulin glargine is modified from human insulin by INJECTIONS inserted into the abdominal wall subcutaneous fat. The
replacing asparagine at α-21 with glycine and by adding pump delivers preprogrammed basal insulin (e.g., 1 unit
two arginine amino acids to the C-terminus of the Intensive insulin therapy should be started as soon as per hour), and the patient directs the pump to admin-
β-chain. Insulin glargine is solubilized in an acidic solu- possible after the diagnosis of type 1 diabetes. Intensive ister boluses premeal. The basal rate can be pro-
tion, and after it has been administered subcutaneously, insulin therapy programs require a team approach that grammed to change over the 24 hours (e.g., an increased
it microprecipitates and is slowly absorbed over 24 includes the patient, diabetes nurse educators, regis- basal rate may be needed in the early morning hours).
hours to simulate basal production of insulin. Insulin tered dietitians, medical social workers, and physicians
detemir is modified from human insulin by removing with an interest in diabetes management. A portable Hypoglycemia is the most serious complication of
the threonine at β-30, and a C14 fatty acid is attached closed-loop system that continuously measures blood both forms of intensive insulin programs. Hypoglyc-
to the amino acid at β-29. Insulin detemir remains glucose and administers appropriate insulin doses has emia can result in falls, motor vehicle accidents, and
soluble after subcutaneous injection; the long duration not yet been developed. Thus, CSII and MDI require seizures. Autonomic neuropathy may mask the usual
of action relates to the molecular modifications. self-monitoring of blood glucose (SMBG) and adjust- adrenergic-type symptoms (e.g., tremor, tachycardia,
ing and/or supplementing the premeal insulin treat- sweat) to alert the patient to hypoglycemia; this is
AMYLIN ANALOGUES ment. With MDI, a long-acting insulin analogue is termed hypoglycemic unawareness. All patients should
administered at bedtime, and rapid-acting analogues have readily available carbohydrate (e.g., glucose
Amylin is cosecreted with insulin by the β-cell and has are administered before meals. With CSII, an external tablets) and injectable glucagon kits.
complementary actions to insulin by delaying gastric
emptying, reducing appetite, and suppressing glucagon
secretion. In addition to insulin, patients with type 1
diabetes are also deficient in amylin. Pramlintide is an
amylin analogue that is administered subcutaneously at
each meal. The addition of pramlintide improves HbA1c
to a modest degree and decreases preprandial insulin
requirements.

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Plate 5-22 Endocrine System

INSULINOMA Microscopic view showing nests of islet cells
separated by delicate fibrous strands and capillaries

Hypoglycemia due to excess endogenous insulin pro- Transabdominal and endoscopic ultrasonography Insulinoma
duction is usually caused by a neoplasm of the pancre- can usually localize 90% of these tumors. In selected
atic β-cells, termed insulinoma. Insulinomas are rare (4 patients, additional localization tests may be needed. Whipple triad:
cases per million people per year), usually benign For example, the selective arterial calcium stimulation Neuroglycopenia
(∼95%), and sporadic (∼95%). Approximately 5% of with hepatic venous sampling can regionalize the insuli- Low plasma glucose
insulinoma patients have multiple endocrine neoplasia noma within the pancreas (see Plate 5-23). Intraopera- concentration
type 1 (MEN 1) (see Plate 8-1). Insulinomas are usually tive pancreatic ultrasonography provides confirmatory Relief of symptoms with
solitary (∼85%) but may be multiple (∼10%) (especially localization. caloric ingestion
in MEN 1) or malignant (∼5%). Pancreatic β-cell
hyperplasia can also cause hypoglycemia (see Plate The treatment of choice for insulinoma is complete Malignant insulinoma
5-23). In patients with insulinomas, insulin secretion surgical resection; it may be possible to enucleate the with intrapancreatic
fails to decrease normally as plasma glucose concentra- tumor and spare normal pancreas tissue or a partial and liver metastases
tions decrease.
Microscopic view showing irregular
Patients with insulinomas typically note discrete nests of more polymorphic, partly
episodes of neuroglycopenia (visual change, confusion, atypical islet cells
and unusual behavior) and sympathoadrenal symptoms pancreatectomy may be required. When the insulinoma
(tremulousness, sweating, and palpitations). Less com- is located in the pancreatic head and enucleation is not
monly, patients with insulinoma have episodes of uncon- possible, a Whipple procedure (resection of the head of
sciousness and rarely hypoglycemia-induced seizures. the pancreas, duodenectomy, gastrectomy, and splenec-
Whipple triad—neuroglycopenia and sympathoadrenal tomy) may be required. Malignant insulinomas should
symptoms consistent with hypoglycemia, documented be removed if possible. When metastatic, the liver is
low plasma glucose concentration at the time of symp- the most common site. Additional treatment approaches
toms, and relief of symptoms with caloric ingestion— for metastatic and unresectable insulin-secreting neo-
should be documented in all patients with suspected plasms include embolization, radiofrequency ablation,
hypoglycemia. The hypoglycemia in patients with cryoablation, endoscopic ultrasound-guided ethanol
insulinoma is caused primarily by an insulin-induced ablation, diazoxide, octreotide, or chemotherapy.
decrease in hepatic glucose output in the fasting state.

Confirmation of endogenous hyperinsulinemic
hypoglycemia requires the documentation of hypogly-
cemia (laboratory-based measurement of venous plasma
glucose <45 mg/dL) with inappropriate levels of plasma
insulin, C-peptide, and proinsulin. These findings can
usually be obtained with fasting—either a short over-
night fast in a supervised outpatient setting or a 72-hour
fast in a hospital setting—or after a mixed-meal test (for
the minority of insulinoma patients who have primarily
postprandial symptoms). Most patients with insulinoma
become hypoglycemic within 48 hours of fasting. Labo-
ratory values, obtained when the patient becomes
symptomatic during a fast, that are consistent with
insulinoma include plasma glucose level below 45 mg/
dL, plasma insulin above 3 μU/mL, plasma C-peptide
above 200 pmol/L, proinsulin above 5 pmol/L, and
β-hydroxybutyrate below 2.7 mmol/L. At the time of
documented hypoglycemia, a drug screen should be
obtained for sulfonylureas and other insulin secretago-
gues (e.g., nateglinide, repaglinide). In addition, at the
end of the fast, 1 mg of glucagon should be adminis-
tered intravenously. Insulin is antiglycogenolytic, and
hyperinsulinemia permits retention of glycogen within
the liver. Whereas normal individuals have released
virtually all glucose from the liver at the end of a
72-hour fast and do not have a glucose response gluca-
gon, insulinoma patients have an increase in plasma
glucose of more than 25 mg/dL within 30 minutes of
glucagon administration.

The differential diagnosis of disorders that can cause
hypoglycemia is broad and includes insulinoma, nesidi-
oblastosis, insulin-autoimmune hypoglycemia, drugs
(e.g., sulfonylurea, insulin, or alcohol), critical illness
(e.g., hepatic failure, renal failure, or sepsis), counter-
regulatory hormone deficiency (e.g., Addison disease),
and large mesenchymal tumors.

Preoperative localization of an insulinoma is impor-
tant for operative planning. Localization of the insuli-
noma within the pancreas may be difficult because they
are usually small (40% are <1.0 cm in largest lesional
diameter). Approximately 75% of insulinomas can be
detected on contrast-enhanced computed tomography.

150 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-23 Pancreas

PRIMARY PANCREATIC β-CELL
HYPERPLASIA

Primary pancreatic β-cell hyperplasia is a rare cause of Insulin increased
hypoglycemia in children and adults. The hyperplastic Glucagon
process may be focal or diffuse. Nesidioblastosis, the
neoformation of islets of Langerhans from pancreatic
duct epithelium, is present in some patients with pan-
creatic β-cell hyperplasia.

CONGENITAL HYPERINSULINISM Diffuse hyperplasia with increased insulin
and hypogycemia
Congenital hyperinsulinism is a rare (one in 50,000 live
births) autosomal dominant or autosomal recessive dis- Selective arterial calcium stimulation test
order usually caused by mutations in the genes that Right hepatic vein
encode the adenosine triphosphate–sensitive potassium
channels (e.g., sulfonylurea receptor type 1 subunit 7X Splenic artery
[SUR1], potassium channel subunit [Kir6.2]). These
loss-of-function mutations result in closure of the 6X
potassium channel and persistent β-cell membrane
depolarization and insulin release despite the prevailing 5X Right hepatic vein
hypoglycemia. Diffuse β-cell hyperplasia and intracta- insulin as a multiple
ble hypoglycemia result. Congenital hyperinsulinism
may also be caused by activating mutations in the genes of basal insulin level
that encode glutamate dehydrogenase or glucokinase.
4X
Focal adenomatous islet-cell hyperplasia may result
from focal loss of the normal maternally inherited allele 3X Gastro- Superior
and somatic expression of the paternally inherited
abnormal genes encoding SUR1 or Kir6.2 (ABCC8 and Splenic duodenal mesenteric
KCNJ11, respectively), which cause β-cell hyperplasia artery
only in the involved cells. Whereas focal islet-cell 2X artery artery
hyperplasia can be cured by resection of the focally
hyperplastic areas of the pancreas, diffuse hyperplasia Superior 1X 20 40 60 20 40 60 20 40 60
may require more extensive pancreatic resections. mesenteric Seconds
artery
Signs of hypoglycemia in neonates include changes
in level of consciousness, tremor, hypotonia, seizures, Gastroduodenal artery
apnea, and cyanotic spells. Symptoms are usually
evident in the first days after birth. Detection may be hyperplasia. Nesidioblastosis is usually present. Similar postprandial hypoglycemia should not be based on
delayed until later in childhood in those with partial or presentation and pathologic findings have been found results of oral glucose tolerance testing but rather on
mild defects in the ABCC8 or KCNJ11 genes. Early after Roux-en-Y gastric bypass surgery for obesity, results after a mixed meal.
diagnosis can prevent neurologic damage from recur- in which symptomatic postprandial hypoglycemia can
rent episodes of hypoglycemia. Macrosomia is common develop 6 months to 8 years after surgery. The underly- β-Cell hyperplasia may be diffuse, asymmetric, or
in newborns with congenital hyperinsulinism. ing pathophysiology is uncertain but may relate to focal. Imaging studies are usually not helpful in local-
decreased ghrelin, unidentified small intestine factors, izing β-cell hyperplasia. Selective arterial calcium stim-
The differential diagnosis of hypoglycemia in infancy or an inability to reset from the preoperative state of ulation with hepatic venous sampling can regionalize
and childhood includes hyperinsulinism (congenital insulin-resistant hyperinsulinemia. the dysfunctional β-cells to arterial distributions
hyperinsulinism, nesidioblastosis, insulinoma, infant of within the pancreas. Calcium gluconate is selectively
a diabetic mother, maternal drugs [e.g., sulfonylurea]); EVALUATION injected into the gastroduodenal, splenic, and superior
drugs; severe illness; transient intolerance of fasting; mesenteric arteries, with timed hepatic venous sam-
lack of counterregulatory hormones (e.g., hypopituitar- Islet-cell hyperplasia may predispose to hypoglycemia, pling for measurement of insulin. Calcium stimulates
ism); Beckwith-Wiedemann syndrome; or enzymatic primarily in the postprandial state rather than in the the release of insulin from abnormal β-cells but not
defects in the metabolism of carbohydrate (e.g., glyco- fasting state as is seen with insulinoma. With the excep- from normal β-cells. An abnormal result is defined as
gen storage diseases, glycogen synthase deficiency), tion of the timing of hypoglycemia, the laboratory more than a two- to threefold increase from baseline in
protein (e.g., branched-chain α-keto acid dehydro- abnormalities are identical to those of patients hepatic venous insulin concentrations. The selective
genase complex deficiency), or fat (e.g., defects in with insulinomas (see Plate 5-22). The diagnosis of arterial calcium stimulation test can lead to a gradient-
fatty acid oxidation). Transient intolerance of fasting is guided partial pancreatectomy.
seen in premature infants and relates to incomplete
development of glycogen stores and gluconeogenic
mechanisms.

NONINSULINOMA PANCREATOGENOUS
HYPOGLYCEMIA SYNDROME AND
POST–GASTRIC BYPASS HYPOGLYCEMIA

Noninsulinoma pancreatogenous hypoglycemia syn-
drome (NIPHS) is a form of islet-cell hyperplasia that
presents with postprandial symptoms caused by hyper-
insulinemic hypoglycemia. The signs and symptoms
are cured with partial pancreatectomy. Pathologic
examination shows β-cell hypertrophy with or without

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SECTION 6

BONE AND CALCIUM

Plate 6-1 Endocrine System

AB

Normal human parathroid gland; H & E stain, ϫ350
Aϭlight and dark chief cells; Bϭoxyphil cells

HISTOLOGY OF THE NORMAL
PARATHYROID GLANDS

The parathyroid glands are derived from branchial Normal human parathroid gland; PAS stain, ϫ675 Bodian stain, BAAF stain,
pouches III and IV and number between two to six H & E stain, ϫ17.5 Glycogen in ϫ1800 ϫ1350
glands, although four is the usual number. In adults, chief cells Secretory granules
each of these ovoid (bean-shaped) glands measures 4 to Ultrastructure of parathyroid gland in chief cells Mitochondria
6 mm × by 2 to 4 mm × 0.5 to 2 mm and weighs
approximately 30 mg (the lower parathyroid glands are in oxyphil cells
generally larger than the upper glands). They vary in
color from yellow to tan, depending on vascularity and Basement membrane of capillary
percentage of oxyphil cells and stromal fat. Pericapillary space

In infants and children, the glands are composed of Endothelial cell
sheets of closely packed chief cells, with little interven-
ing stroma. Oxyphil (or oncocytic) cells first make their Lumen of capillary
appearance at the time of puberty. Fat cells begin to Intercellular spaces
appear in the stroma in late childhood. Both the oxyphil Secretory granules
cells and the fat cells increase in number until they may Collagen fibrils
occupy more than 50% of the volume of the glands Basement membrane
during the fifth and sixth decades of life. of cells

In adults, the glands are composed of cords, sheets, Desmosome
and acini of chief cells in a loose areolar stroma contain- Cell membranes
ing numerous mature fat cells. Chief cells appear in an Endoplasmic reticulum
active synthetic phase (“dark chief cell”) with well- Glycogen
formed endoplasmic reticulum and prominent Golgi Secretory granules
apparatus or in a resting phase (“light chief cell”) with Nucleus
less well-developed endoplasmic reticulum. Scattered Golgi apparatus
individually or in groups among these chief cells are the Mitochondria
oxyphil cells. The chief cell measures approximately 8
μm in diameter. It has a well-defined cell membrane illustration. The chief cells are arranged in cords and is oval to dumbbell-shaped and has a single membrane
and a 4- to 5-μm centrally located nucleus. The chro- nests and separated from the interstitium by basal surrounding a thin clear space inside of which is a dense
matin is densely packed, appearing almost pyknotic, or laminae. The chief cells have straight plasma mem- area composed of short rodlike profiles. The granule
it is finely fibrillar with peripheral margination. Nucle- branes and are attached to other cells by desmosomes. migrates out of the cell through the basement mem-
oli are rare. The cell cytoplasm is clear and amphophilic During the active phase, in addition to the usual brane into the wide pericapillary space. It then goes
in hematoxylin and eosin (H&E) preparations. The organelles, the Golgi apparatus enlarges, numerous through the capillary basement membrane and into the
periodic acid–Schiff (PAS) reaction reveals abundant vacuoles and vesicles appear in the Golgi apparatus, and fenestrated endothelial cells that line the capillaries,
glycogen in these cells. Chief cells also contain abun- many mature secretory granules (50–300 nm in diam- from which parathyroid hormone is liberated into the
dant intracytoplasmic neutral lipid droplets demon- eter) appear in the cell. The mature secretory granule bloodstream.
strated with azure B or Erie garnet A procedures or
with oil red O or Sudan IV stains. Immunohistochemi-
cal studies show stronger staining for parathyroid
hormone in chief cells than in oxyphilic cells.

The oxyphilic cells are larger than chief cells (12–20
μm in diameter) and are polygonal in shape. The cell
membranes are usually clear, and the nucleus is identi-
cal to that of the chief cell. The cytoplasm is composed
of highly eosinophilic fine granules, which stain carmine
with Bensley acid aniline fuchsin (BAAF) and dark blue
with phosphotungstic acid hematoxylin. These cells
contain tightly packed mitochondria filling the cyto-
plasm and have high levels of oxidative enzymes. Unlike
chief cells, the oxyphilic cells have very little intracyto-
plasmic lipid or glycogen. Variants of the oxyphilic cells
include transitional oxyphilic cells, which are smaller
and contain less eosinophilic cytoplasm.

The ultrastructure of the active form of the chief cell
and the mode of secretion are schematized in the

154 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-2 Bone and Calcium

PHYSIOLOGY OF THE Key

PARATHYROID GLANDS Ca = Calcium ions (Ca2+)

Secretion of parathyroid hormone (PTH) from the four P = Phosphate ions (HPO42Ϫ
parathyroid glands is regulated by the blood level of and H2PO41Ϫ)
ionized calcium (Ca2+). Serum ionized calcium concen- H = Hydroxyapatite
trations below the reference range stimulate PTH G.I. tract
secretion, and levels above the reference range inhibit Stimulation
PTH secretion. The principal action of PTH is the Inhibition PTH Kidney
regulation and maintenance of a normal serum total
calcium level between 8.9 and 10.1 mg/dL. The ?P Ca Normal Calcium Ca
calcium-sensing receptors (CaSRs) in the parathyroid excretion
glands are responsible for maintaining this calcium- Gastric Normal P Ca serum controlled P
dependent regulation of PTH secretion. The CaSRs in Ca2+ by serum
the kidneys serve to adjust tubular calcium reabsorption acidity adult threshold
independent of PTH.
Ca
A normal serum concentration of ionized calcium is
critical for many extracellular and cellular functions, Bile s2e.5ru–m4.5Pi P Ca 8.9–10.1 7.0
and it is normally maintained in the very narrow range mg/dL mg/dL
through a tightly regulated calcium–PTH homeostatic
system. Neuromuscular activity is just one function that mg/dL Regulatory mechanism P
is dependent on calcium homeostasis; cytosolic free
calcium serves as a key second messenger. Thus, distur- Pancreatic Vit. D PTH promotes GI absorption of P
bances in extracellular calcium concentration result in calcium by 1␣ hydroxylation
symptoms of abnormal neuromuscular activity. For juice of 25(OH)D
example, hypercalcemia may cause muscle weakness
and areflexia, anorexia, constipation, vomiting, drowsi- Vitamin D Ca Ca Ca P PTH
ness, depression, confusion, or coma. Hypocalcemia enhances inhibits
may result in anxiety, muscle twitching, Chvostek and P P
Trousseau signs, carpal or pedal spasm, seizures, stridor, absorption of P reabsorption Ca
bronchospasm, or intestinal cramps. calcium and Acid of Pi
pH
The daily dietary calcium intake ranges between 300 phosphate:
and 1500 mg/d; total net gastrointestinal (GI) calcium
absorption averages 200 mg/d. The urinary calcium Gastro- Ca
excretion averages 200 mg/d (2% of the filtered load).
Although the urinary calcium excretion is rather con- intestinal P Circulation
stant, the excretion of calcium in the stool depends P Ca
greatly on the body’s need and the dietary intake; nor- secretions Ca
mally, 500 to 700 mg of calcium is excreted per 24 hours
(100–200 mg/d is endogenous fecal calcium that is unaf- required for Succus Alkaline Ca
fected by dietary or serum calcium). The average dietary this action entericus pH
intake of phosphate is 800 to 900 mg/d. GI tract phos-
phate absorption is enhanced by 1,25-dihydroxyvitamin Ca P
D (1,25[OH]2D). Phosphate absorption is impaired by
increasing dietary calcium. Whereas the fecal excretion Ca PTH enhances
of inorganic phosphate (Pi) is roughly 30% of dietary
intake, the urinary phosphate excretion varies widely Stool P P Ca resorption
with intake and serum PTH concentration.
Normal excretion Osteoclastic (secondary action) Urine
If dietary calcium is restricted in healthy individuals, and osteoblastic
a decrease in the blood calcium concentration leads to on average diet activity in Normal excretion
a compensatory increase in intestinal calcium absorp- dynamic
tion. This occurs because a small decrease in serum Ca2+ 500–700 mg/24 h equilibrium on average diet
ionized calcium triggers the CaSR, and there is a Ca2+= 25–300 mg/24 h
prompt increase in PTH secretion. The increased Pi 200–600 mg/24 h Alkaline phosphatase Pi= 500–1,100 mg/24 h
blood PTH concentration leads to increased renal 1α
hydroxylation of 25-hydroxyvitamin D (25[OH]D) to Deposition of
the more potent 1,25(OH)2D (calcitriol). Calcitriol acts Ca2+ and Pi
on enterocytes to increase active transport of calcium. promoted
In addition, renal tubular calcium reabsorption is
increased both by PTH and by a direct effect of hypo- by alkaline pH, Resorption of calcium and
calcemia via the CaSRs in the loop of Henle. The direct phosphate stimulated by PTH
actions of PTH and calcitriol at bone increase bone stress, anabolic
resorption and calcium release. Because of these three
mechanisms of action, the serum ionized calcium con- hormones, and
centration increases, and the serum PTH concentration
decreases. local tissue

With increased dietary calcium exposure, there is concentration
suppression of PTH secretion, inhibition of the 1α
hydroxylation of 25(OH)D, decreased intestinal H Osteoclast
absorption of calcium, increased renal excretion of HH
H Osteoblast H
H Ca H H
Ca PH HP H HH H
HH HH
H H H H HH
HH H H H
HH
H
Bone salts deposited as hydroxyapatite

in proteinaceous bone matrix

Matrix growth requires protein, vitamin C, anabolic hormones (androgens, estrogen, IGF-1) ϩ stress of
mobility. Matrix resorption favored by catabolic hormones (11-oxysteroids [cortisol], thyroid), parathyroid
hormone ϩ immobilization

calcium, decreased renal excretion of phosphate, and In states of excessive PTH secretion, resorption
decreased bone resorption. of calcium and phosphate from bone matrix occurs
through stimulation of the osteoclasts. The osteoclastic
If the parathyroid glands are not functioning prop- overresponse then evokes a tendency for the osteoblasts
erly or are absent, the serum calcium level decreases, to become overactive and leads to bone repair, with the
usually below the renal threshold of 7 mg/dL, and subsequent rise of the alkaline phosphatase level in the
urinary calcium is absent. The presence of a large res- serum. Bone repair is promoted by enhanced absorp-
ervoir of calcium in the skeleton (∼1000 g) as hydroxya- tion of calcium and phosphate from the GI tract facili-
patite (Ca10[PO4]6 [OH]2), however, prevents the serum tated in part by the increased serum concentration of
calcium from falling below 5 mg/dL even in the absence 1,25(OH)2D.
of the parathyroid glands.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 155

Plate 6-3 Endocrine System

BONE REMODELING UNIT

Bone is composed of a collagen matrix, distributed in a Bone is a dynamic tissue Osteoblasts
lamellar pattern and strengthened by pyridinoline in which new mineral is Osteoclast
crosslinks between the triple-helical collagen mole- constantly being laid Bone-lining cells
cules, on which calcium and phosphorus are deposited down while previously
to form hydroxyapatite. The bone matrix also includes mineralized sections Bone section
calcium-binding proteins such as osteocalcin. The are being resorbed
resulting bone mineral is complex crystals of hydroxya- Mineralized bone
patite that contain fluoride and carbonate. Bone-lining cells
Osteoclasts enzymatically
Bone modeling is the process of change in bone size degrade bone matrix proteins
and shape in childhood, where linear growth is the
result of cartilaginous growth at the epiphyses, and Osteocytic
bone width enlargement results from endosteal resorp- lacunae
tion and periosteal apposition. During puberty and
early adulthood, endosteal apposition occurs, and peak Youth Quiescent phase Early resorptive phase
bone mass is achieved. bone
Adult Bone remodeling cycle
Bone remodeling is the lifelong process of bone bone
repair, which has three phases: resorption, reversal, Osteoblasts migrate
and formation. The bone remodeling unit (osteon) Completed osteon into bone defect
involves a cycle of coupled osteoclastic and osteoblastic and synthesize
activities. collagen and matrix
proteins (osteoid)
Osteoblasts develop from determined osteoblast
progenitor cells that originate from mesenchymal
stem cells. The osteoblast progenitor cells are
localized to the periosteum and bone marrow. Osteo-
blasts have receptors for parathyroid hormone, 1,
25-dihydroxyvitamin D, testosterone, estrogen, gluco-
corticoids, growth hormone, thyroid hormone, and
insulinlike growth factors. After osteoblasts lay down
collagen and noncollagen proteins, some of the osteob-
lasts become osteocytes that are buried in the bone
matrix. The remaining osteoblasts either become the
less metabolically active, flattened lining cells or
undergo apoptosis.

Osteoclasts, derived from monocytes and macro-
phages, are multinucleated, large cells that dissolve
bone mineral and degrade matrix. Osteoclast progeni-
tors can be found in the bone marrow and the spleen.
Osteoclastic differentiation is triggered by the produc-
tion of macrophage colony–stimulation factor. Exces-
sive osteoclastic activity is associated with Paget disease,
hyperparathyroidism, and a subset of osteoporosis.

RESORPTION Formative phase Late resorptive phase

The bone remodeling cycle is activated by osteoblast Reversal phase
cells that release collagenase, macrophage colony–
stimulating factor, and receptor activator of NF-κ B glycoprotein-rich material (cement) on the resorbed DEFECTIVE BONE REMODELING
(RANK) ligand. RANK ligand interacts with the RANK surface and signal for osteoblast differentiation. The
receptor and activates osteoclast formation and the ini- new osteoblasts adhere to this material. The reversal In a normal bone remodeling unit, resorption and
tiation of bone resorption. RANK ligand also binds to phase is approximately 4 weeks in duration. formation are tightly coupled. However, a mismatch
osteoprotegerin, which is an osteoclastogenesis inhibi- between resorption and formation can lead to abnor-
tory factor. Macrophage colony–stimulating factor is FORMATION mally thin or dense bones. For example, if the osteo-
also required for normal osteoclast activation. This clastic resorption depth is excessive, it can perforate and
initial osteoblast activation of osteoclasts can be affected During the formation phase, osteoblasts lay down weaken trabecular structure; if the osteoblasts do not
by multiple hormones and factors. For example, par- osteoid (collagen and matrix proteins) until the resorbed completely fill the deep resorption cavity, bone density
athyroid hormone induces the osteoblastic production bone is completely replaced. The formation phase takes and quality decline. If the resorptive process is incom-
of RANK ligand and inhibits production of osteopro- approximately 16 weeks to complete. Normally, the plete because the osteoclasts are not fully activated (e.g.,
tegerin. Vitamin D also increases the production of new bone formed is equivalent to what was resorbed. with macrophage colony–stimulating factor deficiency)
RANK ligand. When the formation phase is complete, the bone or if they are dysfunctional, excessively dense bones
surface is covered with bone-lining cells, and very little may result (osteopetrosis).
Osteoclasts enzymatically degrade bone matrix cellular activity occurs until another bone remodeling
protein and remove mineral within cortical bone or on cycle begins.
the trabecular surfaces. This process is self limited—
perhaps by high local concentrations of calcium or bone
matrix substances—and is completed over 2 weeks.

REVERSAL

After osteoclastic resorption, the reversal phase is
initiated by mononuclear cells that lay down a

156 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-4 Adenoma Hyperplasia Bone and Calcium
(93% of cases) (6% of cases)
PATHOPHYSIOLOGY OF PRIMARY Carcinoma
HYPERPARATHYROIDISM (1% of cases)

The annual incidence of primary hyperparathyroidism Skin
(HPT) is approximately four in 100,000. HPT is twice
as common in women, and most patients are diagnosed Ca2+ Vit. D Liver
after age 45 years. Primary HPT is caused by a single Gut Pi
parathyroid adenoma (89%), multiple (“double”) 25(OH)D Parathyroid hormone (PTH)
parathyroid adenomas (4%), multigland parathyroid elevated
hyperplasia (6%), or parathyroid carcinoma (1%). The
distinction between these forms of primary HPT Renal tubule High 1,25(OH)2D promotes Ca2+ Serum and
directs the surgical approach. absorption of Ca2+ from gut Pi extracellular fluid

Most parathyroid adenomas are encapsulated and ↑Ca2+ filtered into tubule Ca2+ Serum Ca2+
arise from chief cells; the others are composed of exceeds its resorptive capacity increased;
oxyphilic cells. Parathyroid adenomas are usually local- and results in hypercalciuria fails to suppress
ized to the neck, but ectopic parathyroid tumors may PTH secretion
arise anywhere in the anterior mediastinum or even in Pi Ca 2+
the posterior mediastinum. The cells in the adenomas
are monoclonal and are a result of somatic mutations 25(OH)D normal Pi
in genes that control growth. For example, the cyclin 1,25(OH)2D elevated Pi
D1 proto-oncogene (CCND1) encodes a major regula-
tor of the cell cycle. Overexpression of cyclin D1 is Serum Pi low
found in approximately 30% of parathyroid adenomas. or normal
Multiple endocrine neoplasia (MEN) type 1 (see Plate
8-1) is caused by germline mutations in MEN1, a tumor PTH
suppressor gene, and somatic mutations are found in
approximately 15% of sporadic parathyroid adenomas. Ca2+ High PTH promotes Ca2+ Ca2+
Pi Pi
Multiple-gland hyperplasia, characterized by enlarge- reabsorption, inhibits Pi
ment of all four glands, is occasionally mistaken for reabsorption. Also Ca2+ Ca2+ Pi
multiple adenomas. Chief cell hyperplasia is much more promotes conversion of Pi
common than clear cell hyperplasia (the latter is associ- 25(OH)D to active
ated with hyperplasia primarily of the superior parathy- Ca2+ metabolite 1,25(OH)2D Compensatory High PTH
roid glands). Parathyroid hyperplasia may be sporadic Pi increase in stimulates
or associated with a familial syndrome (e.g., MEN 1, osteoblastic osteoclastic
MEN 2A, HPT–jaw tumor syndrome, or familial iso- Ca2+ activity with resorption of
lated hyperparathyroidism). Distinguishing between Pi variable rise in bone (Ca2+, Pi,
parathyroid gland hyperplasia and normal parathyroid serum alkaline and matrix)
tissue can be difficult for the pathologist. In general, phosphatase
abnormal parathyroid glands are increased in size and Nephrocalcinosis
contain less fat. Primary HPT affects almost all patients
with MEN 1, and the hypercalcemia is typically present Calculi Variable reduction in bone density. In rare, severe cases, cysts and brown
by the third decade of life, but primary HPT affects Urine tumors (due to osteitis fibrosa cystica) and subperiosteal resorption
only 10% of patients with MEN 2A and tends to occur Ca2+ elevated
later in life. Parathyroid adenomas and hyperplasia
are multiple and cystic in patients with HPT–jaw of these three mechanisms of action, the serum ionized the tubular reabsorption of inorganic phosphate (Pi),
tumor syndrome. The jaw tumor is usually fibrous in calcium concentration increases, and the serum PTH causing an excessive loss of phosphate. The net effect
nature. concentration decreases. of these chemical changes is an increase in serum
calcium and a decrease in serum phosphate, with
The diagnosis of parathyroid carcinoma is based on Patients with primary HPT have abnormal regula- increasing amounts of both calcium and phosphate
local invasion of contiguous tissues or metastases tion of PTH secretion by calcium, a finding partly being excreted in the urine. This predisposes to the
(lymph node or distant). Both sporadic and germline caused by an elevation in the set point. The set point formation of calcium phosphate and calcium oxalate
inactivating mutations in CDC73 (previously known as for calcium-dependent feedback suppression of PTH renal stones. At times, there may be precipitation of
HRPT2) are responsible for HPT–jaw tumor syndrome, release is 15% to 30% above normal. It is important to calcium in the soft tissues of the kidneys, producing
which is associated with an increased risk for parathy- note that PTH secretion in primary HPT is not com- nephrocalcinosis.
roid carcinoma. pletely autonomous and can usually be partially inhib-
ited by a further rise in serum calcium. The excessive Roughly 25% of patients with primary HPT have
A normal serum concentration of ionized calcium production of PTH leads to hypercalcemia by increased evidence of bone disease, with marked bone resorption
(Ca2+) is critical for many extracellular and cellular stimulation of the osteoclastic activity of bone (with the and a compensatory increase in osteoblastic activity.
functions, and it is normally maintained in the very release of calcium and phosphate), increased absorption Bone mineral is formed by small hydroxyapatite
narrow range through a tightly regulated calcium–PTH of calcium from the gut, and increased reabsorption of crystals that contain carbonate, magnesium, sodium,
homeostatic system. In healthy individuals, a small calcium by the renal tubules. In addition, PTH inhibits and potassium.
decrease in serum ionized calcium triggers the calcium-
sensing receptor, and there is a prompt increase in PTH
secretion. The increased blood PTH concentration
leads to an immediate increase in bone resorption and
renal 1α-hydroxylation of 25-hydroxyvitamin D to the
more potent 1, 25-dihydroxyvitamin D (calcitriol). Cal-
citriol leads to increased intestinal calcium absorption
over several days. Finally, PTH leads to an immediate
decrease in urinary calcium excretion by stimulating
calcium reabsorption at the distal renal tubule. Because

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 157

Plate 6-5 Endocrine System

PATHOLOGY AND CLINICAL
MANIFESTATIONS OF PRIMARY
HYPERPARATHYROIDISM

Approximately 80% of patients with primary hyperpar- Nephrocalcinosis
athyroidism (HPT) are asymptomatic, and hypercal-
cemia is detected by routine biochemical testing. Less Nephrolithiasis
commonly, primary HPT is diagnosed during the eval-
uation of symptomatic hypercalcemia, renal lithiasis, “Salt and pepper” skull Bone biopsy Absence of lamina dura
osteoporosis, or osteitis fibrosa cystica. Although most (focal resorption) (broken line indicates
patients with primary HPT do not have overt symp- normal contour)
toms, it may be responsible for more subtle symptoma-
tology (e.g., weakness, fatigue, depressed mood, or mild Bone rarefaction; Subper- Brown tumor (giant cell “Codfishing” Calicum deposits
cognitive dysfunction). cysts fractures iosteal tumor or osteoclastoma) of vertebrae in blood vessels;
resorption hypertension
The more overt signs and symptoms of long-stand-
ing, untreated primary HPT have been referred to as Peptic ulcer MEN 1 with
“bones, stones, abdominal moans, and groans.” The parathyroid gland
“stones” refer to nephrolithiasis, which occurs in 20% hyperplasia and
of patients with primary HPT. The nephrolithiasis is multiple adenomas
caused by the hypercalciuria (a result of increased fil- (pituitary, thyroid,
tered calcium in the setting of hypercalcemia) that pre- pancreas, adrenals)
disposes to the development of calcium oxalate stones.
The most common effect on bones is osteopenia and Limbus keratopathy
osteoporosis. Less common bone-related sequelae of
severe, long-standing primary HPT include absence of Pancreatitis
the lamina dura around the teeth; subperiosteal resorp-
tion of the bone, especially around the radial margins calcitriol concentration (a result of PTH-stimulated of hypercalcemia. Treating the vitamin D deficiency in
of the phalanges, around the sternal end of the clavicle, renal hydroxylation of 25-hydroxyvitamin D). Serum this setting can aggravate the hypercalcemia and
and along the margins of other bones; diffuse “salt-and- creatinine concentrations can be increased in patients hypercalciuria.
pepper” decalcification of the skull, resembling multi- with marked and long-standing primary HPT and
ple myeloma; fractures of the terminal phalanges with can be associated with nephrocalcinosis. Patients with The treatment of primary HPT rests on the surgical
telescoping, giving the appearance of pseudoclubbing severe primary HPT may also have a normochromic removal of the parathyroid adenoma (for single-gland
(the phalangeal joints may show increased flexibility); normocytic anemia. disease) or, rarely, of 3.5 hyperplastic parathyroid
large bone cysts (osteitis fibrosa cystica) in various loca- glands in the setting of diffuse parathyroid hyperplasia
tions (fractures through these cysts or fractures through Vitamin D deficiency is frequently present in patients (e.g., with multiple endocrine neoplasia [MEN] type 1).
rarefied bone may occur); diffuse demineralization of with primary HPT, a state that can attenuate the degree
the skeleton, especially of the spine, with “codfishing”
of the vertebral bodies; and brown tumors (also known
as giant cell tumors, osteoclastoma, or epulis), which
are radiolucent bone tumors that may develop in the
jaw and other bones.

Hypercalcemia may also cause nausea, anorexia, con-
stipation, nephrogenic diabetes insipidus (polyuria and
polydipsia), glucose intolerance, peptic ulcer disease,
pancreatitis, and hypertension. Parathyroid crisis occurs
with severe hypercalcemia (calcium >15 mg/dL), and
affected patients present with central nervous system
dysfunction (e.g., confusion, coma). Parathyroid
crisis—typically precipitated by volume depletion—is
treated with volume repletion with isotonic saline
and an agent to decrease bone resorption (e.g., a
bisphosphonate).

Physical examination typically reveals no specific
findings for primary HPT. Parathyroid adenomas are
not palpable; when a parathyroid tumor is palpable, it
is usually parathyroid carcinoma. With a slit-lamp
examination of the eyes, calcium phosphate deposition
may be seen in a semicircular form around the limbus
of the cornea and is termed band keratopathy.

Laboratory abnormalities in patients with primary
HPT include increased serum total and ionized calcium
concentrations, decreased serum phosphorus concen-
tration (parathyroid hormone [PTH] inhibits the proxi-
mal renal tubular reabsorption of phosphate), serum
PTH concentration that is either above the reference
range or inappropriately (in the setting of hypercal-
cemia) within the reference range, and increased serum

158 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-6 Bone and Calcium

TESTS FOR THE DIFFERENTIAL DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIC STATES
DIAGNOSIS OF THE CAUSES OF
HYPERCALCEMIA Condition Serum Serum Serum Serum Serum Associated findings
Ca2+ PTH 25(OH)D 1,25(OH)2D
The most common causes of hypercalcemia are primary Primary Pi
hyperparathyroidism (HPT) and malignancy. The first hyperpara-
question the clinician should ask is whether the hyper- thyroidism High N 80% Asymptomatic
calcemia is a persistent finding; thus, a serum calcium or
(Ca2+) concentration should be remeasured. If levels N or N N or Nephrolithiasis
of serum calcium have been measured in the past,
they should be reviewed. Whereas long-standing mild Osteoporosis
hypercalcemia (<11 mg/dL) is typical of primary HPT,
an abrupt onset of severe hypercalcemia (>13 mg/dL) Hypercalcemic sx
is more typical of hypercalcemia of malignancy.
The patient’s diet and medications should be reviewed Cancer with History of primary
for clues suggestive of milk–alkali syndrome and extensive
medication-related hypercalcemia. bone N or N or N tumor, destructive
metastases N or lesions on radiograph,
For patients with persistent hypercalcemia, the first
step is to determine whether it is parathyroid hormone Multiple bone scan
(PTH) mediated. Whereas PTH-mediated hypercal- myeloma and
cemia is primary HPT, non–PTH-mediated hypercal- lymphoma Abnormal serum or
cemia is usually caused by underlying malignancy, urine protein electro-
granulomatous disease, or vitamin D intoxication. N or N phoresis, abnormal
bone radiographs
PARATHYROID HORMONE–MEDIATED
HYPERCALCEMIA Humoral N or ↑PTHrP
hypercalcemia N or N Solid malignancy
Most patients with primary HPT have serum PTH con- of malignancy
centrations above the reference range. However, 20% of usually evident
patients with primary HPT have serum PTH concentra-
tions in the upper portion of the reference range, but Sarcoidosis N or N Hilar adenopathy
they are inappropriately in the reference range for the and other
setting of hypercalcemia. Measurement of serum inor- granulomatous interstitial lung disease,
ganic phosphate (Pi) concentration and 24-hour urinary diseases elevated angiotensin-
excretion of calcium are usually helpful in confirming converting enzyme
PTH-mediated disease. Hypophosphatemia results
from the PTH-related inhibition of renal proximal Hyperthyroidism N Symptoms of hyper-
tubular phosphate reabsorption. Although hypophos- N N thyroidism, elevated
phatemia may also be seen with PTH-related protein
(PTHrP)–mediated hypercalcemia, it is not seen with serum thyroxine
the other forms of non–PTH-mediated hypercalcemia.
The 24-hour urinary excretion of calcium is either at the Vitamin D N or Very N or History of excessive
high end of the reference range or above the reference intoxication N or N
range in most patients with primary HPT. However, N vitamin D intake
this finding is not specific to primary HPT and is Milk—alkali
seen with most other causes of hypercalcemia. The syndrome N or History of excessive
24-hour urinary excretion of calcium is typically less or N calcium and alkali in-
than 100 mg in patients with milk–alkali syndrome or N or gestion, heavy use of
familial hypocalciuric hypercalcemia or in patients over-the-counter calci-
treated with thiazide diuretics. Serum 1,25-dihydroxyvi- Total body immobilization um-containing antacids
tamin D (calcitriol; 1,25[OH]2D) concentrations are
usually increased in patients with primary HPT because Multiple fractures,
PTH increases the 1α-hydroxylation of 25-hydroxyvita- paralysis (children,
min D (calcidiol; 25[OH]D) in the kidney. adolescents,
patients with Paget
NON–PARATHYROID HORMONE– disease of bone)
MEDIATED HYPERCALCEMIA
If the serum concentration of PTHrP is low, serum calcium—the physiologically relevant fraction. Rarely,
When the serum PTH concentration is low in a concentrations of 25(OH)D and 1,25(OH)2D should an increased measured amount of total blood calcium
patient with hypercalcemia, additional stepwise testing be measured. Whereas a markedly increased serum may be attributable to increased amounts of calcium
to consider includes measurement of 25(OH)D, concentration of 25(OH)D is consistent with vitamin bound to protein (e.g., in multiple myeloma with
1,25(OH)2D, PTHrP, serum thyrotropin (TSH) (for D intoxication, increased serum concentrations of increased calcium-binding paraprotein) and the ionized
hyperthyroidism), and vitamin A and performance of 1,25(OH)2D may be seen with the enhanced extrarenal fraction is normal; this is termed pseudohypercalcemia.
serum protein electrophoresis (for multiple myeloma). 1α-hydroxylation of 25(OH)D that occurs in granulo-
matous disorders and lymphoma. In this setting, sar- Familial hypocalciuric hypercalcemia (FHH) is a
PTHrP—the hormone responsible for humoral coidosis is usually evident on a plain chest radiograph rare autosomal dominant disorder associated with an
hypercalcemia of malignancy—is an agonist at the PTH or computed tomography; these images usually demon- inactivating mutation in the gene encoding the
receptor and may be hypersecreted by solid malignan- strate bilateral hilar adenopathy and reticular pulmo- calcium-sensing receptor. Typically identified because
cies. However, unlike PTH, PTHrP does not induce nary opacities. of incidental discovery of hypercalcemia, these patients
renal conversion of 25(OH)D to 1,25(OH)2D. have hypocalciuria with the fractional urinary excretion
If vitamin D and PTHrP levels are low in a patient of calcium less than 1%. Patients with FHH have mild
with non–PTH-mediated hypercalcemia, then serum hypercalcemia with either normal or slightly increased
protein electrophoresis should be performed, and concentrations of serum PTH. The mutation respon-
serum TSH and vitamin A concentrations should be sible for FHH makes the calcium-sensing receptor
measured. In this setting, hypercalcemia is usually asso- less sensitive to calcium. Thus, a higher than normal
ciated with stimulation of bone resorption (e.g., multi- serum calcium concentration is required to reduce
ple myeloma, hyperthyroidism, vitamin A intoxication, PTH release; an increase in tubular calcium and
or immobilization) or increased calcium intake in the magnesium reabsorption in the kidney results in hyper-
setting of renal insufficiency (milk–alkali syndrome). calcemia, hypocalciuria, and hypermagnesemia. These
patients are asymptomatic; FHH has a benign natural
OTHER CAUSES OF APPARENT history, and no treatment is required. All first-degree
HYPERCALCEMIA relatives should be tested for hypercalcemia and alerted
that it is not primary HPT and that no surgery is
Increased serum total calcium concentration is usually needed.
the result of an increased amount of free (ionized)

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 159

Plate 6-7 Endocrine System

Key Phosphate filtration blocked
Ca ϭ Calcium (Ca2ϩ) by glomerular disease
P ϭ Phosphate (HPO42– )
H ϭ Hydroxyapatite PTH
secondarily
Parathyroids secondarily increased
stimulated by low serum
Ca2ϩ and lack of negative Hyperplasia of
feedback from 1,25(OH)2D
all parathyroid
glands

VDitamin ? High serum Creatinine Acidosis
Pi depresses
P P serum Ca2ϩ P PTH inhibits
Pi reabsorption
Pi absorption P P Ca 7.0 and promotes
not impaired PP Ca mg/dL Ca2ϩ reabsorption
RENAL OSTEODYSTROPHY Ca P Circulation but to no avail
P Ca P because little filters
The kidneys have a central role in regulating mineral P through glomerulus
metabolism. Renal osteodystrophy refers to the bone Ca2ϩ bound in PP P P
morphology alterations found in patients with chronic gut by high Pi Ca Ca
kidney disease. Common forms of renal osteodystrophy P
in patients with progressive renal failure include high P P Ca P
bone turnover with secondary or tertiary hyperparathy- P
roidism (HPT) and the associated osteitis fibrosa PP
cystica, low bone turnover with adynamic bone disease, P
low bone turnover combined with increased amounts Ca P P
of unmineralized bone (osteomalacia), bone cysts
related to β2-microglobulin–associated amyloid depos- Depositon Urine
its, and mixed osteodystrophy in which components of Ca2ϩ Ca2ϩ Very
of high and low bone turnover are found. The two and Pi Pi low
key factors in renal osteodystrophy are decreased renal normal or
conversion of 25-hydroxyvitamin D(25[OH]D) to Compensatory Increased stimulation
1,25-dihydroxyvitamin D (1,25[OH]2D) and decreased enhanced: increase in of osteoclastic activity
ability to excrete inorganic phosphate (Pi). osteoblastic by PTH: resorption of
also in
As renal failure progresses, the glomerular filtration activity with Ca2ϩ and Pi enhanced
rate (GFR) decreases, resulting in a decreased filtered ectopic by acidosis
load of phosphate. As the serum phosphate concen- variable rise of
tration rises, the serum calcium (Ca2+) concentration sites serum alkaline
decreases, and the serum parathyroid hormone (PTH) phosphatase
secretion increases. The secondary HPT state is also a
result of decreased blood concentration of 1, 25(OH)2D; H Osteoclast
when GFR decreases below 30 mL/min, the decreased
renal mass leads to decreased renal 1α-hydroxylation of H Ca P Osteoblast Ca Subperiosteal
25(OH)D. Over the short term, the increased serum Fractures H P resorption
PTH concentrations provide a temporary and partial H
correction in the biochemical abnormalities by decreas- H HH Cyst formation
ing renal tubule reabsorption of filtered phosphate, H H
increasing bone reabsorption of calcium, and stimulat-
ing the renal 1α-hydroxylation of 25(OH)D. However, Diminished bone density; osteitis fibrosa cystica
over the long term, these effects are pathologic as renal
failure progresses, and PTH effects have no influence Tertiary hyperparathyroidism results when there is tissues, joints, viscera, and arteries. Blood vessel involve-
on the failed kidneys. This maladaptive situation is refractory hypersecretion of PTH associated with ment can lead to ischemia and gangrene. Tertiary HPT
made worse by the renal failure–associated hyperphos- severe parathyroid gland hyperplasia and neoplastic results in subperiosteal resorption, cyst formation,
phatemia directly decreasing the renal conversion of transformation with monoclonal parathyroid adeno- variably diminished bone density, osteitis fibrosa cystica
25(OH)D to 1,25(OH)2D, leading to less 1,25(OH)2D mas. Because of the limited effect of PTH on enhancing with brown tumors, and fractures. Spine radiographs
inhibition on PTH secretion. phosphate excretion in failing kidneys and the contin- may show banded sclerosis of the upper and lower
ued effect on reabsorption of calcium and phosphate margins of the vertebral bodies with rarefaction
from bone, hypercalcemia develops. The increased between. Skull radiographs may show spotty decalcifi-
calcium–phosphate product leads to metastatic calcifi- cation (“salt-and-pepper” skull).
cation with calcium–phosphate precipitation into soft

160 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-8 Bone and Calcium

BONY MANIFESTATION OF RENAL OSTEODYSTROPHY

Radiograph shows spotty Brown tumor of proximal phalanx
decalcification of skull
Secondary hyperparathyroidism (“salt-and-pepper” skull)

Radiograph shows
banded sclerosis of
spine and sclerosis of
upper and lower
margins of vertebrae,
with rarefaction
between. Note
compression
fracture.

Osteitis fibrosa cystica Subperiosteal Osteitis fibrosa cystica
of distal femur resorption of of tibia with brown
phalanges (chiefly tumor

RENAL OSTEODYSTROPHY on palmar aspect

(Continued) of middle phalanx)

Subperiosteal resorption of the phalanges may be Loss of lamina dura of
evident—primarily on the palmar aspect of the middle teeth (broken lines
phalanx. In children, renal osteodystrophy results in indicate normal contours)
growth retardation and skeletal deformities.
Resorption of lateral
The most common bony abnormality in patients end of clavicle
treated with peritoneal dialysis or hemodialysis is ady-
namic bone disease—bone turnover does not occur, and Osteomalacia Pseudo- Slipped capital
bone cell activity is absent. Unlike what is observed fractures femoral epiphysis
with osteomalacia, osteoid formation does not increase. (Milkman
Adynamic bone disease is, in part, a result of excess Fracture of syndrome,
PTH suppression with calcium-based phosphate long bones Looser
binders and vitamin D analogues. Adynamic bone zones on
disease predisposes to bone fractures (e.g., hip fracture). radiograph)
This disorder can be confirmed by bone biopsy or by a
serum PTH concentration less than 100 pg/mL. The Fractured ribs
key to treatment is to allow PTH to increase by decreas-
ing or discontinuing calcium-based phosphate binders crest after the administration of tetracycline markers to The goals of treatment should be to maintain normal
and vitamin D analogues. determine the rate of new bone formation (see Plate serum calcium and phosphorus concentrations while
6-22)—may be needed to determine the pathogenesis minimizing the exposure to aluminum. These targets
Osteomalacia is the result of decreased bone turnover of renal osteodystrophy. are achieved by a low-phosphate diet, addition of phos-
and an increase in unmineralized bone caused by either phate binders when GFR is below 25% of normal, and
vitamin D deficiency or aluminum intoxication (the Other contributing factors to bone disease in patients vitamin D supplementation to maintain a normal blood
latter from aluminum-containing antacids). There is with renal failure include vitamin K deficiency (required concentration of 1,25(OH)2D. With advanced renal
decreased bone density with thinning of the cortex. for carboxylation of bone matrix proteins) and bone failure and tertiary HPT, parathyroidectomy may be
Looser zones are a characteristic radiologic finding morphogenetic protein-7 (required for normal osteob- indicated.
in osteomalacia (see Plates 6-8 and 6-22). Looser last differentiation and produced in the normal kidney).
zones are pseudofractures or narrow radiolucent lines
(2–5 mm in width) with sclerotic borders that lie per-
pendicular to the cortical margin. Frequently bilateral
and symmetric, they are located in the scapula, femoral
neck, medial part of the femoral shaft, ribs, pubic and
ischial rami, and clavicle. Bone resorption may be seen
at the lateral ends of the clavicles. Milkman syndrome
refers to the findings of bilateral and symmetric pseu-
dofractures in a patient with osteomalacia. Fractures
may occur with minimal or no trauma and usually
involve the long bones (e.g., hip), ribs, and vertebral
bodies. A bone biopsy—usually obtained from the iliac

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 161

Plate 6-9 Endocrine System

HISTOLOGY OF THE
PARATHYROID GLANDS IN
HYPERPARATHYROIDISM

Primary hyperparathyroidism (HPT) is caused by a Adenoma. Rim of relatively normal Adenoma. Mixture of oxyphil cells and chief
single parathyroid adenoma (89%), multiple (“double”) parathyroid tissue about compact adenoma; cells in adenoma; H & E stain, ϫ35
parathyroid adenomas (4%), multigland parathyroid H & E stain, ϫ11.5
hyperplasia (6%), or parathyroid carcinoma (1%).
Frequent characteristics
PARATHYROID ADENOMA of chief cells in adenomas

Most parathyroid adenomas are encapsulated and arise Mononuclear Multinuclear
from chief cells; the others are composed of oxyphilic giant cells giant cells and
cells. The adenoma is composed of tightly packed acinar structures
sheets, cords, and acini of predominantly chief cells.
Clear cells and oxyphilic cells, singly and in groups, are Primary hyperplasia: chief cell Primary hyperplasia: clear cell
often present, and some adenomas may be composed
entirely of oxyphilic cells. The tumor may be homoge- Metastases
neous or nodular. The chief cell of an adenoma is (to lymph
usually somewhat larger than a normal chief cell. The nodes,
nuclei are variable in size, and mononuclear giant cells liver,
with hyperchromatic nuclei, not indicative of malig- elsewhere)
nancy, are often present. Multinuclear giant cells are
frequently seen in adenomas. Immunohistochemical Invasion
staining is typically positive for parathyroid hormone
(PTH) and chromogranin A. The most important cri-
terion for differentiating an adenoma from chief cell
hyperplasia is the identification of normal parathyroid
tissue in a patient with an adenoma; this may occur
either as a rim outside the capsule of the adenoma or
in another gland. This “normal” parathyroid in the
presence of an adenoma is composed almost entirely of
large, light, inactive chief cells, with abundant glyco-
gen, small Golgi apparatuses, and rare secretory gran-
ules. The cells in the adenomas are monoclonal and
result from somatic mutations in genes that control
growth. For example, the cyclin D1 proto-oncogene
(CCND1) encodes a major regulator of the cell cycle.
Overexpression of cyclin D1 is found in approximately
30% of parathyroid adenomas. Multiple endocrine neo-
plasia (MEN) type 1 is caused by germline mutations
in MEN1, a tumor suppressor gene, and somatic
mutations are found in approximately 15% of sporadic
parathyroid adenomas.

PRIMARY CHIEF CELL HYPERPLASIA Secondary hyperplasia Mitosis Fibrous bands and
hyperchromicity
Chief cell hyperplasia is much more common than clear cell membranes and empty-appearing cytoplasm
cell hyperplasia (the latter is associated with hyperplasia (wasserhelle cells). The nuclei are small and densely Carcinoma
primarily of the superior parathyroid glands). In hyper- stained. There is a tendency for nuclear palisading, gen-
plasia, all four glands are invariably involved. Each erally at the pole of the cell adjacent to the stroma and Immunohistochemical staining is typically positive for
gland is composed of cords; sheets; and acini of tightly vessel, giving a “bunch of berries” appearance. Immu- PTH and chromogranin A.
packed chief, oxyphilic, and clear cells. The cells are nohistochemical staining is usually weak for PTH and
similar in size to or slightly more enlarged than normal strong for chromogranin A. CARCINOMA
cells. The gland is often nodular, owing to separation
of the cells by stroma or to aggregation of cell types. In SECONDARY PARATHYROID The diagnosis of parathyroid carcinoma is based on
primary chief cell hyperplasia, the appearance of each GLAND HYPERPLASIA local invasion of contiguous tissues or metastases
gland may be identical to that of an adenoma except for Secondary parathyroid gland hyperplasia is often (lymph node or distant). A large, dense, fibrous capsule
the absence of normal parathyroid tissue. Immunohis- indistinguishable from primary chief cell hyperplasia, (with invasion of the capsule) and broad, dense, fibrous
tochemical studies show diffuse staining for PTH although nodularity is somewhat less common in bands traversing the tumor are present. The cells are
and chromogranin A. Parathyroid hyperplasia may be secondary hyperplasia, and each gland is often large and uniform and have distinct cell membranes.
sporadic or associated with a familial syndrome (e.g., composed of uniform sheets of small, dark chief cells. The nuclei are large, regular, and hyperchromatic.
MEN 1, MEN 2A, hyperparathyroidism–jaw tumor Oxyphilic cells and clear cells are occasionally seen. Mitotic figures are almost invariably seen. A rim of
syndrome, or familial isolated hyperparathyroidism). normal parathyroid tissue may rarely be noted. Both
somatic and germline inactivating mutations in CDC73
PRIMARY CLEAR CELL HYPERPLASIA (formerly HRPT2) are responsible for hyperparathy-
roidism–jaw tumor syndrome, which is associated with
The four glands are composed of sheets; cords; and an increased risk for parathyroid carcinoma.
acini of uniform, large (10–40 μm) cells, with distinct

162 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-10 Bone and Calcium

PATHOPHYSIOLOGY OF Postoperative Less commonly:
HYPOPARATHYROIDISM (more common) Autoimmune destruction
Abnormal parathyroid gland development
Abnormal regulation of PTH production,

secretion, or action

The chemical picture of hypoparathyroidism is a low Skin
serum calcium concentration (usually <7 mg/dL),
a high serum inorganic phosphorus (Pi) concentration Liver PTH deficiency
(typically >5 mg/dL), and decreased excretion of
calcium and phosphorus in the urine. These chemical Ca2ϩ Vit. D 25(OH)D Serum and
features can be explained by the absence of the major Gut Pi extracellular fluid
actions of parathyroid hormone (PTH). The calcium Ca2ϩ
level is low because of the following: (1) decreased Pi Serum Pi high due to
PTH-dependent stimulation of the osteoclastic activity increased renal tubular
of bone, causing little resorption of calcium and (2) Low 1,25(OH)2D impairs reabsorption
decreased PTH-dependent stimulation of the renal absorption of Ca2ϩ from gut
conversion of 25-hydroxyvitamin D (25[OH]D) to the Pi
more potent 1,25-dihydroxyvitamin D (1,25[OH]2D), Serum Ca2ϩ below
with resultant diminished absorption of calcium from renal threshold Ca2ϩ
the gastrointestinal tract. Because the serum calcium
level is usually below the kidney threshold of 7 mg/dL, Ca2ϩ Serum Ca2ϩ low due
little urinary calcium is found. By contrast, the serum Pi to decreased renal
phosphorus concentration is elevated because there is tubular reabsorption,
excessive reabsorption of phosphate by the renal 25(OH)D normal reduced absorption
tubules, which is not blocked by PTH. The high serum 1,25(OH)2D decreased from gut, and reduced
phosphorus level has the additional effect of depressing bone resorption
the serum calcium level. A great deal of calcium is
“bound” in the gastrointestinal tract by the high phos- Ca2ϩ Ca2ϩ Ca2ϩ
phate concentration, and the action of vitamin D on Pi Pi
calcium absorption is less effective in the presence Pi
of high phosphate concentrations. The combination Absence or deficiency of Ca2ϩ
of a low serum calcium concentration, a high serum PTH causes diminished Pi
phosphorus level, and a normal alkaline phosphatase reabsorption of Ca2ϩ,
concentration in the absence of renal failure or excessive reabsorption Rate of osteo- Little osteo-
malabsorption is pathognomonic of a state of of Pi, and decreased blastic bone clastic bone
hypoparathyroidism. conversion of 25(OH)D formation resorption due
to active 1,25(OH)2D decreased to to lack of
PTH deficiency is most commonly seen as a compli- match rate of PTH stimulus
cation after neck surgery (e.g., subtotal or total thyroid- Renal resorption
ectomy, parathyroid gland surgery, or neck cancer tubule
surgery). Surgery-induced hypoparathyroidism may be
transient (if viable parathyroid tissue persists) or per- Alkaline
manent. Transient hypoparathyroidism may compli- phosphatase
cate as many as 20% of operations for thyroid cancer normal
that require total or near-total thyroidectomy. Tran-
sient hypoparathyroidism is also seen in patients after Urine Bone density normal or slightly increased
resection of a parathyroid adenoma associated with Ca2+ low
severe and long-standing hypercalcemia. In this setting,
the normal parathyroid glands are suppressed, and Abnormal parathyroid gland development may be PSEUDOHYPOPARATHYROIDISM—
calcium is avidly taken up by the bones (“hungry bone caused by X-linked or autosomal recessive mutations HYPOCALCEMIA DESPITE A HIGH
syndrome”). Less commonly, the cause of hypopar- (e.g., mutations in GCM2, a gene encoding a transcrip- SERUM PARATHYROID HORMONE
athyroidism may relate to autoimmune destruction; tion factor). Mutations in the gene responsible for the CONCENTRATION
abnormal parathyroid gland development; or abnormal synthesis of preproPTH may result in defects of the
regulation of PTH production, secretion, or action. production of biologically active PTH. In addition, In patients with pseudohypoparathyroidism, the hypoc-
autosomal dominant activating mutations in gene alcemia stimulates release of PTH from the parathyroid
When hypoparathyroidism is acquired in a patient encoding the CaSR decrease the set point for calcium glands. However, because PTH is ineffective in mobi-
who has not had neck surgery, it most commonly feedback; thus, PTH secretion is not triggered until the lizing calcium from bone or in increasing the renal
results from autoimmune destruction of the parathy- patient is markedly hypocalcemic. Because of the acti- conversion of 25(OH)D to 1,25(OH)2D, hypocalcemia
roid glands. Autoimmune hypoparathyroidism usually vated CaSR at the kidney, the urinary calcium excretion persists. The causes of this clinical scenario include
occurs as part of the polyglandular autoimmune syn- is high (unlike what is observed in all other forms of PTH resistance and vitamin D deficiency (see Plates
drome type 1; these patients are also at increased risk hypoparathyroidism). 6-12 and 6-13).
for primary adrenal insufficiency and chronic mucocu-
taneous candidiasis (see Plate 8-6). A rarer cause of
acquired primary hypoparathyroidism is the develop-
ment of activating autoantibodies to the calcium-
sensing receptor (CaSR).

GENETIC CAUSES OF
HYPOPARATHYROIDISM

Congenital hypoparathyroidism is associated with
abnormal parathyroid development or PTH synthesis.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 163

Plate 6-11 Endocrine System

Trousseau sign

Chvostek sign

CLINICAL MANIFESTATIONS OF
ACUTE HYPOCALCEMIA

The classic manifestations of acute hypocalcemia vary Laryngeal
from minor to severe symptoms with tetany, seizures, spasm
laryngospasm, papilledema (choked disk), or heart (stridor)
failure. The degree of symptoms relates not only to the
severity of hypocalcemia but also to the rapidity of Hyperreflexia
onset. The dominant clinical features of chronic hypo-
calcemia are cataracts, basal ganglia calcification, Convulsions
extrapyramidal disorders, and changes in dentition. QT

Tetany is the result of acute increased peripheral Electrocardiogram: prolonged Q-T interval
neuromuscular irritability; early and mild symptoms
include anxiety, muscle spasms and cramps, hyper- Choked disk
reflexia, photophobia, diplopia, perioral and acral par-
esthesias, and hyperirritability. Advanced and more development. Chronic hypocalcemia usually results in The most common cause of severe hypocalcemia is
severe symptoms of tetany include carpopedal spasm dry and coarse skin. The fingernails may become brittle acute hypoparathyroidism related to the removal of a
(the forced adduction of the thumb, extension of the and have transverse grooves. Scalp hair can be sparse, parathyroid neoplasm or accidental removal of the
fingers, and flexion of the wrist and metacarpophalan- coarse, and brittle. parathyroid glands at the time of thyroid surgery.
geal joints), laryngospasm and stridor (caused by mus-
cular spasm of the glottis), and seizures (grand mal, In addition to hypocalcemia-related heart failure, the The diagnosis of severe and symptomatic hypocal-
petit mal, or focal). Tetany usually does not occur Q-T interval on electrocardiography may be pro- cemia is an endocrine emergency, and immediate treat-
unless the serum total calcium concentration falls below longed. QRS and ST changes may mimic acute myo- ment is indicated to prevent seizures, laryngospasm,
7.0 mg/dL. However, tetany may be aggravated by cardial infarction. Hypocalcemia can trigger torsades de cardiac events, and death. Correction of the hypocal-
alkalosis, hypomagnesemia, and hypokalemia. Patient pointes. cemia reverses the signs and symptoms.
anxiety related to the perioral and acral paresthesias
may lead to hyperventilation, resulting in respiratory
alkalosis that further aggravates tetany. Acidosis can
completely suppress the clinical manifestations of
hypocalcemia.

The Trousseau sign is the induction of carpopedal
spasm by inflating a sphygmomanometer cuff above the
systolic blood pressure for 3 minutes. For example, if
the systolic blood pressure is 120 mm Hg, the sphyg-
momanometer cuff should be inflated to 140 mm Hg
and kept it at that pressure for 3 minutes. The ischemia
induced by the Trousseau maneuver increases the excit-
ability of the forearm nerve trunks. With a positive
Trousseau sign, patients are unable to open the hand.

The Chvostek sign is the demonstration of ipsilateral
facial muscle contraction by tapping the facial nerve just
anterior to the ear and below the zygoma. In severe
hypocalcemic states, contracture of the orbicularis oculi
and even contraction of the contralateral facial muscles
may be seen. Both the Trousseau and Chvostek signs
are not specific for hypocalcemia; they can also be elic-
ited in alkalotic states (e.g., hyperventilation, primary
aldosteronism with severe hypokalemia).

Dental anomalies (e.g., defective enamel, dental
hypoplasia) can occur if hypocalcemia is present in early

164 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-12 Bone and Calcium

PATHOPHYSIOLOGY OF Primary defect
PSEUDOHYPOPARATHYROIDISM Renal tubule cells and (usually) bone unresponsive to PTH

Pseudohypoparathyroidism (PHP) is the result of Hyperplasia of parathyroid PTH secondarily
end-organ resistance to parathyroid hormone (PTH). glands caused by low increased but still
The key laboratory findings are hypocalcemia, hyper- Skin serum Ca2ϩ ineffective on renal
phosphatemia, and increased blood PTH concentra- tubular cells and bone
tion. There are two forms of PHP, known as type 1 and Liver
type 2.
Ca2ϩ Vit. D 25(OH)D
PSEUDOHYPOPARATHYROIDISM TYPE 1 Pi
Gut Ca2ϩ Serum and
PHP type 1 is characterized by decreased renal produc- Pi extracellular fluid
tion of cyclic adenosine monophosphate (cAMP) when
exogenous PTH is administered. The pathophysiology 1,25(OH)2D low, Ca2ϩ absorption from gut impaired Serum Pi high because
of this type of PHP relates to mutations in the gene of increased renal
encoding the α-subunit of the G protein (GNAS) that
is coupled to the PTH receptor. Mutations in GNAS tubular reabsorption
lead to lack of adenyl cyclase activation when PTH
binds to its receptor. This lack of signal transduction (PTH effect Pi
prevents PTH activity. GNAS is associated with blocked)
tissue-specific parental imprinting. For example, GNAS Ca2ϩ
expression in the kidney, pituitary, gonads, and thyroid Pi Ca2ϩ
is determined by the maternal allele. This tissue-
specific parental imprinting has led to a subclassifica- 25(OH)D normal Serum Ca2ϩ low
tion of PHP type 1 into three subtypes. 1,25(OH)2D decreased because of decreased
tubular reabsorption
PHP type 1a, also known as Albright hereditary and low intestinal
osteodystrophy, is caused by an autosomal dominant, absorption of Ca2ϩ
maternally transmitted loss-of-function mutation in
GNAS. PHP type 1a has a unique phenotype with short PTH
stature, a rounded face, obesity, ocular abnormalities,
short fourth and fifth metacarpals, dental hypoplasia, Ca2ϩ Ca2ϩ reabsorption decreased, Ca2ϩ
developmental delay, mental retardation, and subcuta- Pi Pi reabsorption increased, Pi
neous calcifications (see Plate 6-13). The secondary and conversion of 25(OH)D
hyperparathyroidism found in PHP type 1a is to 1,25(OH)2D decreased Ca2ϩ Ca2ϩ Pi
ineffective in producing phosphaturia because the because of end-organ Pi
renal tubule is relatively unresponsive, but in some unresponsiveness to PTH
instances, the other end-organ, bone, can show over-
stimulation of the osteoclasts, and bone resorptive Renal tubule
changes may be seen. PTH is also ineffective in
converting 25-hydroxyvitamin D (25[OH]D) to the Alkaline Osteoblastic Elevated
more potent 1,25-dihydroxyvitamin D (1,25[OH]2D). phosphatase bone PTH has
Because individuals with PHP type 1a PHP also have usually formation no effect
resistance to other G-coupled hormones (at the thyroid, normal normal or on bone
pituitary, and gonads), they may have signs and symp- decreased resorption
toms of thyroid and gonadal dysfunction. because of
end-organ
Pseudopseudohypoparathyroidism occurs when the unrespons-
inactivating GNAS mutation is paternally transmitted. iveness
Affected individuals have the body phenotype charac- (in most
teristic of Albright hereditary osteodystrophy but cases)
without resistance to PTH action at the kidney because
of the presence of the normal maternal allele. Thus, Bones usually normal, rarely show resorptive changes
these individuals have normal blood concentrations of
calcium, phosphate, and PTH. However, they can have PSEUDOHYPOPARATHYROIDISM TYPE 2 normal renal cAMP response to exogenous PTH
excessive dermal ossification caused by progressive administration. However, PTH does not lead to phos-
osseous heteroplasia. Individuals with PHP type 2 have the same biochemical phaturia. Thus, the PTH receptor–adenyl cyclase
profile as those with PHP type 1, which includes hypo- complex functions normally, but the resistance is at the
PHP type 1b is caused by maternal transmission of calcemia, hyperphosphatemia, and increased blood level of activity of cAMP, suggesting a defect in cAMP-
mutations in the regulatory elements for GNAS. These concentrations of PTH. Individuals with PHP type 2 dependent protein kinase A. PHP type 2 is not familial,
individuals lack the characteristic body phenotype of do not have the body phenotype characteristic of and the age of onset ranges from infancy to senescence.
Albright hereditary osteodystrophy but have PTH Albright hereditary osteodystrophy and do not have Thus, PHP type 2 is an acquired disorder; however, the
resistance at the kidney. Thus, affected patients have resistance to other hormones. In addition, they have a precise cause has not yet been determined.
hypocalcemia, hyperphosphatemia, and increased blood
PTH concentrations.

PHP type 1c is caused by mutations that affect the
coupling of the G protein to the PTH receptor. Thus,
the adenyl cyclase system is intact, but it is not coupled
to the binding of PTH to its receptor. These patients
have the body phenotype characteristic of Albright
hereditary osteodystrophy, hypocalcemia, hyperphos-
phatemia, and increased blood PTH concentrations.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 165

Plate 6-13 Endocrine System

CLINICAL MANIFESTATIONS OF
PSEUDOHYPOPARATHYROIDISM
TYPE 1A

Pseudohypoparathyroidism (PHP) is a congenital dis- “Knuckle, knuckle,
order associated with end-organ resistance to parathy- dimple, dimple” sign
roid hormone (PTH). PHP type 1a, also known as
Albright hereditary osteodystrophy, is caused by an Short 4th and 5th metacarpals
autosomal dominant, maternally transmitted loss-of-
function mutation in GNAS (see Plate 6-12). Affected Short thickset figure;
children usually develop symptomatic hypocalcemia round face
between ages 3 and 8 years as serum phosphate and
PTH concentrations rise. PHP type 1a has a unique Short metacarpal bones,
phenotype with short stature, a rounded face, a short resorptive changes
neck, obesity, a flattened nose bridge, ocular abnor-
malities, short fourth and fifth metacarpals, dental Subperiosteal resorption
hypoplasia, developmental delay, mental retardation,
and subcutaneous calcifications. The most outstanding Nodules in soft tissue
distinguishing feature is brachydactyly with shortening with ulceration
of the fourth and fifth (and sometimes the third) meta-
carpal and metatarsal bones. This can be demonstrated Subcutaneous osseous plaques Short metatarsals; deformity of toes
not only on radiographs but also by having the patient
make a fist, which demonstrates the so-called “knuckle, Pseudopseudohypoparathyroidism occurs when the individuals lack the body phenotype characteristic of
knuckle, dimple, dimple sign,” first described by inactivating GNAS mutation is paternally transmitted. Albright hereditary osteodystrophy but have PTH
Albright. Instead of a proper knuckle appearing, the Affected individuals have the body phenotype charac- resistance at the kidney.
short metacarpal leads to a depression. The short meta- teristic of Albright hereditary osteodystrophy but
carpals result from premature fusion of the epiphyses without resistance to PTH action at the kidney because PHP type 1c is caused by mutations that affect the
and failure of the proper appearance of some of the of the presence of the normal maternal allele. Thus, coupling of the G protein to the PTH receptor. Thus,
epiphyses, not only of the metacarpals but also of the these individuals have normal blood concentrations of the adenyl cyclase system is intact, but it is not coupled
phalanges, which, therefore, are short. The distal calcium, phosphate, and PTH. However, they may have to the binding of PTH to its receptor. These patients
phalanx of the thumb is typically short (“potter’s excessive dermal ossification caused by progressive have the body phenotype characteristic of Albright
thumb”). Other long bones also can be short (e.g., ulna) osseous heteroplasia. hereditary osteodystrophy, hypocalcemia, hyperphos-
or deformed (e.g., bowed radius). The skull can show phatemia, and increased blood PTH concentrations.
hyperostosis frontalis interna. In addition to these fea- PHP type 1b is caused by maternal transmission of
tures, there may be multiple exostoses, resembling a mutations in the regulatory elements for GNAS. These
dyschondroplasia, and striking subcutaneous calcifica-
tion and ossification, at times in the form of osseous
plaques or nodules, which may be seen and felt in soft
tissues or skin (osteoma cutis). Stone-hard papular or
nodular lesions occur at sites of minor trauma (e.g., over
the anterior surface of the lower legs). Ocular abnor-
malities include microphthalmia, strabismus, hyperte-
lorism, diplopia, nystagmus, optic atrophy, and macular
degeneration.

Because the GNAS gene has a role in many functions
throughout the body, patients with PHP type 1a can
also have clinical presentations dominated by resistance
to other hormones (e.g., thyrotropin, gonadotropins,
or growth hormone–releasing hormone). Hypothy-
roidism is common in individuals with PHP type 1a;
serum thyrotropin concentrations are above the refer-
ence range, and free thyroxine concentrations are below
the reference range. Women with PHP type 1a can have
delayed puberty, oligomenorrhea, and infertility. Men
with PHP type 1a frequently have low serum testoster-
one concentrations and infertility. Most patients with
PHP type 1a have growth hormone deficiency. G pro-
teins are also associated with signal transduction path-
ways for vision, olfaction, and taste. Thus, patients with
PHP type 1a may have symptoms related to olfactory,
gustatory, and auditory dysfunction. Mild to moderate
mental retardation is common and presumably related
to the effect of the GNAS mutation on brain tissue.

Although PTH can lack activity at the renal tubule,
it can be functional at the bone. Therefore, all of the
manifestations of secondary hyperparathyroidism may
be seen at times, especially if the skeleton responds to
this stimulation. Subperiosteal resorptive changes in
the digits and changes in the epiphyses, which are indis-
tinguishable from renal osteitis fibrosa, can be seen.

166 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-14 Bone and Calcium

RISK FACTORS FOR OSTEOPOROSIS
Disuse

Prolonged casting
or splinting (localized
osteoporosis)

Prolonged bed rest or Paralysis (paraplegia Space travel
general inactivity
quadriplegia, hemiplegia, (weightlessness)

lower motor neuron

disease)

Diet Drugs Idiopathic Genetic disorders

PATHOGENESIS OF Deficiency of Heparin Adolescent Middle- Osteogenesis
OSTEOPOROSIS calcium and Metho- (10–18 yr) aged imperfecta
vitamin D trexate man Homocystinuria
Osteoporosis is a common structural skeletal disorder
characterized by low bone mass and bone fragility that Alcoholism Ethanol Neoplasms
increase the risk of bone fracture (see Plates 6-15 to Anorexia Glucocorticoids
6-17). Bone structural integrity is jeopardized as the nervosa
bony microarchitecture is disrupted (e.g., the trabecular
plates become perforated and discontinuities develop in Chronic illness
the trabecular struts). The cause of low bone mass in
patients with osteoporosis is usually a combination Rheumatoid Cirrhosis Renal tubular Bone marrow
of factors that include low peak bone mass, increased arthritis Sarcoidosis acidosis tumors
bone resorption, and decreased bone formation. High- (myeloma,
turnover osteoporosis occurs when increased bone lymphoma,
resorption is dominant, and low-turnover osteoporosis leukemia,
occurs when decreased bone formation predominates. mast cell)
Approximately 50% of peak bone mass is genetically
determined, and 50% is determined by environmental Pituitary Adrenal cortex Endocrine abnormalities Parathyroid Thyroid
factors (e.g., physical activity and calcium intake).
Ovary Testis
The main contributor to osteoporosis in post-
menopausal women is estrogen deficiency. When Corticotropin- Glucocorticoid Estrogen deficiency Testosterone Hyperpara- Hyper-
present, estrogen inhibits bone resorption by affecting secreting excess (postmenopausal, deficiency thyroidism thyroidism
osteoclast function. Prolonged estrogen deficiency in pituitary (hyperplasia, premature ovarian (primary or (primary or
premenopausal women (e.g., hypogonadotropic hypo- tumor tumor, failure, secondary secondary secondary)
gonadism that may occur with eating disorders, low iatrogenic) hypogonadism) hypogonadism)
body fat, excessive exercise, hypopituitarism, or hyper-
prolactinemia) also results in decreased bone mass. Osteoporosis Osteoporosis
Estrogen also has a role in maintaining bone density in in postmeno- in men
men; osteoporosis occurs in men who lack estrogen pausal women
(e.g., aromatase deficiency). Testosterone deficiency in
men predisposes them to osteoporosis. Hyperparathyroidism (primary or secondary) results bone involvement (e.g., multiple myeloma, leukemia,
in decreasing bone mass and, if untreated, in systemic mastocytosis, lymphoma).
Advancing age, a history of fragility (low-impact osteoporosis.
trauma) fracture, glucocorticoid therapy, low body mass The osteoporosis that occurs in women with anorexia
index, family history of hip fracture, cigarette smoking, The prevalence of osteoporosis is increased in nervosa results not only from dietary insufficiencies of
excessive alcohol use, and low bone mineral density patients affected by medical disorders that are associ- calcium and vitamin D but also from the estrogen defi-
(BMD) are the most consistent and strongest predictors ated with inflammation (e.g., rheumatoid arthritis, ciency with secondary hypogonadism.
of bone fracture risk. inflammatory bowel disease, sarcoidosis), malabsorp-
tion (e.g., celiac disease, cystic fibrosis), renal excretion Genetic disorders that cause osteoporosis include
Additional risk factors for osteoporosis include of calcium (e.g., renal tubular acidosis), thyroid osteogenesis imperfecta (see Plates 6-25 and 6-26) and
dietary deficiency in calcium and vitamin D, medica- hormone excess (endogenous or exogenous), or direct homocystinuria.
tions (e.g., anticonvulsants, heparin, methotrexate),
frailty and recurrent falls, prolonged bed rest or general
inactivity, neurologic disorders that limit mobility (e.g.,
paralysis), and weightlessness (e.g., space travel).

Glucocorticoid excess inhibits bone formation by
negatively affecting the differentiation and life span
of osteoblasts. A dosage-dependent relationship exists
between chronic glucocorticoid therapy and fracture
risk. Although excess glucocorticoid exposure is most
commonly caused by medical therapy for an underlying
inflammatory disorder (e.g., asthma, arthritis), it may
also result from endogenous Cushing syndrome (pitui-
tary or adrenal dependent).

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 167

Plate 6-15 Endocrine System

OSTEOPOROSIS IN CLINICAL MANIFESTATIONS OF OSTEOPOROSIS
POSTMENOPAUSAL WOMEN
Axial

Osteoporosis in postmenopausal women refers to Rib fractures common
markedly low bone mass that can occur with estrogen
deficiency and aging. Osteoporosis is usually clinically Vertebral compression fractures cause continuous
silent until a bone fracture occurs; even then, most (acute) or intermittent (chronic) back pain from
vertebral fractures are asymptomatic. The most midthoracic to midlumbar region, occasionally
common sites of bone fracture in postmenopausal to lower lumbar region
women with osteoporosis are vertebral, hip, rib, and
distal radius (Colles fracture). Multiple vertebral frac- Appendicular
tures lead to progressive thoracic kyphosis (dowager’s Fractures caused by minimal trauma
hump), loss of height, and abdominal protrusion. Oste-
oporosis also predisposes to appendicular fractures Proximal femur Proximal Distal radius Progressive thoracic kyphosis, or dowager’s
(e.g., proximal femur, distal radius, and proximal (intertrochanteric humerus hump, with loss of height and abdominal
humerus) that may occur with minor trauma. or intracapsular) protrusion

Bone strength is derived from bone mass (size, shape, Most common types
and microarchitecture) and bone turnover status (rates
of formation and resorption). Bone mass can be esti- World Health Organization’s website, provides person- include monoclonal antibody against the osteoclas-
mated by measuring bone mineral density (BMD) with alized data on 10-year probabilities of hip fracture and togenesis factor receptor activator of NF-κB ligand
dual energy–x-ray absorptiometry (DXA) at the hip and osteoporotic fractures. (RANKL), sclerostin inhibitors, integrin inhibitors, and
lumbar spine. The risk of fracture is inversely propor- cathepsin K inhibitors.
tional to BMD. The BMD T score is the standard Pharmacologic treatment options include antiresorp-
deviation (SD) difference between a patient’s BMD and tive agents and anabolic agents. Antiresorptive medica- Treatment effectiveness can be monitored with bone
that of a young adult reference population. Normal tions include estrogen, selective estrogen receptor markers at baseline and 3 to 6 months after initiation
bone density is defined as a BMD value within 1 SD of modulators, bisphosphonates, and calcitonin. The main of treatment. DXA of the lumbar spine and hip should
the mean in a young adult reference group. Based on anabolic agent is parathyroid hormone 1-34 (teri- be performed 1 year after treatment initiation and
increased risk of fracture, osteoporosis is defined as a paratide). Additional emerging pharmacologic options periodically (e.g., every 2–3 years) thereafter.
BMD T score that is –2.5 SD or more below the mean
of the young adult reference population. The value
obtained when a patient’s BMD is compared with that
of an age-matched population is termed the Z score. A
Z score less than –2.0 SD is considered low.

BMD may be low because the individual’s peak bone
mass reached as a young adult was low, bone formation
is decreased, bone resorption is increased, or a combi-
nation of all three of these factors. Excessive bone
resorption is a major contributor to osteoporosis in
postmenopausal women.

Secondary osteoporosis should be considered in
all patients with low BMD, and evaluation for the
following disorders should be considered: vitamin D
deficiency, osteomalacia, hyperthyroidism, hyperpar-
athyroidism, celiac disease, mast cell disease, and hyper-
cortisolism. The first step of evaluation is a thorough
interview and physical examination. Laboratory evalu-
ation should include complete blood cell count and
measurement of blood concentrations of calcium, phos-
phorus, liver enzymes, creatinine, thyrotropin, and
25-hydroxyvitamin D. The role of additional laboratory
testing is based on the findings from the history and
physical examination. Bone turnover markers may be
helpful for some patients in assessing fracture risk,
selecting treatment, and monitoring response to
therapy.

TREATMENT

Nonpharmacologic treatment—diet, exercise, smoking
cessation, and avoidance of medications that increase
bone loss (e.g., glucocorticoids)—is key to the success-
ful management of osteoporosis. The daily intake of
calcium and vitamin D should average 1500 mg and
800 IU, respectively. Regular weight-bearing exercise
(e.g., walking) helps maintain BMD and reduce the risk
of hip fracture (the latter is likely because of improved
muscular strength).

The decision of when to institute pharmacologic
therapy can be guided by fracture risk assessment. A
fracture risk assessment tool (FRAX), available from the

168 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-16 Bone and Calcium

PROGRESSIVE SPINAL DEFORMITY IN OSTEOPOROSIS

OSTEOPOROSIS IN MEN

Although bone mineral density (BMD) is routinely Age 55 years Age 65 years Age 75 years
measured in postmenopausal women, it is not often
measured in men. Thus, osteoporosis in men is diag- Compression fractures of thoracic vertebrae lead to loss of height and progressive
nosed after low-impact trauma fractures or incidental thoracic kyphosis (dowager’s hump). Lower ribs eventually rest on iliac crests,
finding of osteopenia on radiographs performed for and downward pressure on viscera causes abdominal distension
other reasons. Osteoporosis may also be found in men
because of purposeful case-detection testing in high- TREATMENT −2.5) should be considered when the 10-year probabil-
risk groups (e.g., those taking glucocorticoid therapy ity of hip fracture reaches 3% or when the 10-year
and those with long-standing hypogonadism, hyperpar- The treatment of osteoporosis in men includes lifestyle probability of osteoporotic fractures combined reaches
athyroidism, or malabsorption). Compression fractures measures and pharmacologic therapy. 20%. These 10-year fracture probabilities can be cal-
of the thoracic vertebral bodies lead to loss of height culated with a fracture risk assessment tool (FRAX)
and progressive thoracic kyphosis. With multiple ver- Lifestyle measures include weight-bearing exercise available from the World Health Organization’s
tebral compression fractures, the lower ribs may reach (e.g., walking), smoking cessation, and avoidance of website. FRAX provides personalized data on 10-year
the iliac crests, and abdominal distension becomes more excessive alcohol use. These men should be advised to probabilities of hip fracture and osteoporotic fractures.
evident. take calcium (1500 mg/d) and vitamin D (800 IU/d) In addition, pharmacologic treatment should be consid-
supplementation. If the patient has secondary oste- ered for men who do not meet these FRAX risk cutoffs
Osteoporosis occurs when there is low bone mass and oporosis, treatment of the underlying disorder is the but are at high risk for progressive bone loss (e.g.,
skeletal fragility, leading to an increased risk of fracture mainstay of therapy (e.g., testosterone replacement in chronic high-dose glucocorticoid therapy).
(e.g., vertebral bodies, hips, and ribs). Measurement of men with long-standing hypogonadism).
BMD is a key tool to assess the risk of bone fracture. Bisphosphonates are the primary form of pharmaco-
BMD measurement with dual energy–x-ray absorpti- Pharmacologic therapy is indicated in men age 50 logic therapy for osteoporosis in men. Parathyroid
ometry (DXA) at the lumbar spine and hip should be years or older who have a history of hip or vertebral hormone 1-34 (teriparatide) treatment is reserved for
considered in men in the following clinical settings: fracture or who have been diagnosed with osteoporosis men with progressive bone loss despite secondary
low-trauma fractures, incidental finding of apparent on the basis of BMD (DXA T score of −2.5 or less). factors being addressed and treatment with a
osteopenia on plain radiographs, loss of more than 4 cm Pharmacologic treatment for men with osteopenia bisphosphonate.
of height, or presence of a known risk factor for oste- determined by BMD (DXA T score between −1.0 and
oporosis (e.g., glucocorticoid therapy, long-standing
hypogonadism, hyperparathyroidism, malabsorption).
A DXA T score less than or equal to −2.5 is consistent
with osteoporosis. A DXA T score between −1.0 and
−2.5 is consistent with osteopenia.

A secondary osteoporosis evaluation is indicated in
men with low-impact fractures or a DXA bone mass T
score less than −2.5. These men should be evaluated
for underlying malabsorption (e.g., celiac disease),
hypogonadism, Cushing syndrome, hepatic and renal
disorders, hypercalciuria, hyperparathyroidism, genetic
disorders (e.g., osteogenesis imperfecta), and bone
marrow tumors (e.g., multiple myeloma, mastocytosis).
Many of these diagnoses may be evident on a thorough
interview and physical examination. Initial laboratory
testing should include complete blood cell count; serum
protein electrophoresis; and measurement of blood
concentrations of testosterone, calcium, phosphorus,
parathyroid hormone, 25-hydroxyvitamin D, tissue
transglutaminase antibodies, hepatic enzymes, creati-
nine, and tryptase. A 24-hour urine collection should
be completed to measure cortisol, calcium, and creati-
nine. Findings on these tests may lead to further case-
directed testing (e.g., dexamethasone suppression
testing for suspected Cushing syndrome). Measure-
ment of markers of bone formation and resorption may
be helpful in selected cases.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 169

Plate 6-17 Endocrine System

CLINICAL MANIFESTATIONS OF Marked kyphosis is evident. Anterior wedge and biconcave (codfish) deformities are present.
OSTEOPOROTIC VERTEBRAL
COMPRESSION FRACTURES

Compression fractures of the thoracic and lumbar ver- T4
tebral bodies are the most common type of fracture in T6
patients with osteoporosis. Because of less resistance to
anteroposterior displacement, the most common loca- T8
tion for vertebral fractures is in the region of the tho-
racolumbar junction (thoracic vertebrae 11 and 12 and T10
lumbar vertebrae 1 and 2). Vertebral compression frac-
tures may be asymptomatic and detected incidentally T12
on chest radiographs. In patients with osteoporosis,
vertebral compression fractures may occur spontane- L1
ously or with low-impact trauma. When present, the
pain—dull or sharp in character and aggravated by Multiple grade 3 compression fractures are evident in the thoracic vertebral bodies,
movement—related to a compression fracture may be resulting in marked kyphosis.
severe and radiate around the flanks to the anterior
abdomen. The severe pain related to vertebral com- radicular symptoms are present, magnetic resonance Pain control, with nonopioid medications if possible,
pression fractures usually resolves over 4 to 8 weeks; imaging of the spine may be needed. Bone mineral is important to allow normal physical activity. For
however, chronic back discomfort may be permanent. density testing is indicated in all patients with vertebral patients with severe or persistent pain, vertebroplasty
compression fractures. The underlying cause of the ver- or kyphoplasty should be considered. These interven-
Kyphosis results from multiple thoracic vertebral tebral fracture should be determined to direct disease- tions involve the percutaneous injection of polymethyl-
compression fractures. Both the kyphosis and the loss specific therapy to prevent future fractures. For methacrylate bone cement into the collapsed vertebral
of vertical vertebral body height lead to loss of total example, if postmenopausal osteoporosis is the underly- body, which resolves the acute pain, prevents long-term
body height. Patients with thoracic kyphosis may ing cause predisposing the patient to vertebral frac- pain, and prevents height loss.
present with multiple symptoms. For example, neck tures, treatment with an antiresorptive agent (e.g.,
discomfort may result from the persistent neck exten- bisphosphonates) should be considered.
sion required to keep the head vertical. Also, with
height loss, compression of the abdominal organs
causes increased abdominal prominence and restrictive
pulmonary physiology. The lowest rib may contact the
iliac crest and cause pain near the 12th thoracic verte-
bral body and at the iliac crest.

The occurrence of a vertebral fracture is highly pre-
dictive of future vertebral fractures; approximately 20%
of these patients experience a second fracture within 1
year of their first one.

The types of vertebral fractures include anterior
wedge, biconcave (“codfish”) deformity, and compres-
sion. Fractures can be graded as grade 1, 20% to 25%
deformity; grade 2, 26% to 40% deformity; and grade
3, more than 40% deformity.

EVALUATION AND TREATMENT

Patients with symptoms consistent with acute vertebral
fracture should be evaluated with plain spine films. If

170 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-18 Bone and Calcium

NUTRITIONAL-DEFICIENCY Primary causes Sun Ultraviolet Parathyroid Parathyroid hormone
light gland (PTH) elevated
RICKETS AND OSTEOMALACIA Lack of sunlight hyperplasia
impairs endogenous Skin due to low Glomerular filtration
Calcium and phosphate—the two main mineral com- vitamin D synthesis serum Ca2+ of Ca2+ and Pi low
ponents of bone—are required for normal bone growth because of low
and mineralization. Rickets occurs in children with Dietary lack of serum levels
deficient mineralization at the growth plate and causes vitamin D
widened and irregular epiphyseal plates. Osteomalacia Ca2+
refers to deficient mineralization of bone matrix, result- Marked prematurity Vit. D Serum and Pi
ing in uncalcified osteoid seams, soft bones with bowing, (liver inefficient in Ca2+ extracellular
and pseudofractures. Nutritional-deficiency rickets and converting vitamin D fluid Pi
osteomalacia may result from deficiencies in calcium, to 25[OH]D) Deficient
phosphate, or both. vit. D Ca2+ Pi
Anticonvulsants
Calcipenic rickets and osteomalacia are caused by promote breakdown Ca2+ Ca2+ low Pvei ry
decreased intestinal absorption of calcium, either of vitamin D and Pi Ca2+ and Pi to low normal low
because of lack of dietary calcium or decreased absorp- 25(OH)D in liver
tion of intestinal calcium. Decreased absorption of absorption Vit. D Lack of vitamin D
intestinal calcium occurs with malabsorption (e.g., Lack of bile AI impaired for activation to
celiac disease) and with decreased action of vitamin D at or alimentary Pi 1,25(OH)2D by
its receptor—a result of vitamin D deficiency, a defect in secretions may liver and kidney
the 1α-hydroxylation of vitamin D, or an abnormality at impair absorption of impairs Ca2+
the vitamin D receptor. The hypocalcemia of calcipenic vitamin D and calcium and Pi absorption
rickets and osteomalacia leads to secondary hyperpar-
athyroidism, which may partially correct the hypo- High dietary Alkaline
calcemia, but because of increased urinary inorganic intake of phosphate, phosphatase
phosphate (Pi) excretion, it also results in hypophos- phytate, oxalate, or greatly elevated
phatemia. Thus, with nutritional-deficiency rickets and fatty acids may impair
osteomalacia, the serum phosphorus concentration is absorption of calcium Pi Ca2+ Ca2+ Pi PTH inhibits
below the lower limit of the reference range, and the
serum calcium concentration is in the low-normal range Gastrectomy or GI Pi reabsorption,
or below the lower limit of the reference range. In shunts may decrease further reducing
addition, secondary hyperparathyroidism leads to absorption of calcium
increased osteoclastic reabsorption of bone. Increased and vitamin D serum Pi Urine
osteoblastic activity with deposition of bone matrix
occurs in response to the osteoclast activation. However, Ca2+ very
the bone matrix cannot be mineralized because of low
blood levels of calcium and phosphorus, leading to Antacids (aluminum Ca 2+ low Pi low
rickets in children and osteomalacia in adults. salts impair phos- (may be
phate absorption)
Vitamin D (calciferol) is a fat-soluble compound with Pi elevated
a 4-ringed cholesterol structure. The synthesis of Pregnancy
vitamin D3 (cholecalciferol) from 7-dehydrocholesterol Loss of initially)
occurs in the skin with exposure to ultraviolet rays in Lactation Ca2+ and Pi
sunlight (photoisomerization). Vitamin D in the form to fetus or
of ergocalciferol (vitamin D2) is ingested in the diet, Malabsorption, in milk
primarily from plants, fish, eggs, and fortified products sprue (excessive
(e.g., milk and cereals). Cholecalciferol and ergocalcif- loss of calcium
erol are hydroxylated in the liver by 25-vitamin D and phosphate
hydroxylase to form 25-hydroxyvitamin D (25[OH]D; in stool)
calcidiol). 25(OH)D is 1α-hydroxylated in the proximal
convoluted tubule cells of the kidney to form to the Osteo- Increased Elevated PTH
more potent 1,25-dihydroxyvitamin D (1,25[OH]2D; blasts osteoblastic promotes
calcitriol). Vitamin D deficiency can occur at multiple activity in osteoclastic
levels—decreased exposure to sunlight; decreased response to resorption of
dietary intake of vitamin D; decreased gastrointestinal osteoclastic bone (Ca2+,
absorption of vitamin D (e.g., after gastric surgery or destruction Pi, and matrix)
with long-term, high-dose glucocorticoid therapy); of bone
decreased hepatic 25-hydroxylation of vitamin D (e.g.,
in premature infants, in patients with advanced liver Flaring Pseudo- Osteoclasts Cysts and
disease) or renal 1α-hydroxylation of vitamin D; accel- fractures Subperiosteal brown
erated breakdown of vitamin D at the liver (e.g., with resorption tumors
medications that induce P450 enzyme activity such as Widened and irregular Bowing, soft bones
anticonvulsants]); renal loss of vitamin D (e.g., neph- epiphyseal plate
rotic syndrome); or end-organ insensitivity to vitamin Uncalcified osteoid seams
D (see Plate 6-19).
Rickets or osteomalacia
Vitamin D–deficient rickets usually presents in the
first 3 years of life, when bone growth is high and children require approximately 400 IU of vitamin D D2 (ergocalciferol). The treatment dosage of vitamin
exposure to sunlight may be limited. Vitamin D in per day. Whereas breast milk contains 25 IU of vitamin D2 is adjusted based on patient age and clinical
fetuses is dependent on placental transfer of maternal D per liter, infant formulas contain at least 400 IU of response. Optimizing calcium intake is also important
25(OH)D. Adequate vitamin D in infants is dependent vitamin D per liter. Thus, breastfed infants are at (≥1000 mg/d of total dietary calcium). Treatment
on dietary intake and exposure to sunlight. Infants and increased risk for vitamin D deficiency and should be effectiveness should be monitored by measurement of
supplemented with 400 IU vitamin D daily. serum calcium, phosphorus, 25(OH)D, and alkaline
phosphatase. Urinary calcium excretion can also be
TREATMENT monitored to document recovery. Radiographs should
be obtained to document bone healing.
Effective treatment of vitamin D deficiency rickets and
osteomalacia can usually be accomplished with vitamin

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 171

Plate 6-19 Endocrine System

Primary disorder Liver Vit. D adequate

Vit. D

Type I. Failure of con- 25(OH)D
version of 25(OH)D to
PSEUDOVITAMIN D–DEFICIENCY 1,25(OH)2D in kidneys Hyperparathyroidism PTH
RICKETS AND OSTEOMALACIA Type II. End-organ caused by low elevated
(gut) insensitivity to serum Ca2+
Pseudovitamin D–deficient rickets is caused either by action of 1,25(OH)2D
lack of 1,25-dihydroxyvitamin D (1,25[OH]2D; calci- Serum and
triol) or by target-organ resistance to the actions of 1, Urine extracellular fluid
25(OH)2D. Type 1 pseudovitamin D–deficient rickets Ca2+ low
occurs when renal 1α-hydroxylase deficiency results in Pi low Ca2+ Pi Ca2+
insufficient conversion of 25-hydroxyvitamin D Ca2+ very low Pi very low Pi
(25[OH]D; calcidiol) to the more potent 1,25(OH)2D. Flaring
Type 2 pseudovitamin D–deficient rickets results from 1,25(OH)2D deficient (type I) or end Absorption
end-organ resistance to the action of 1, 25[OH]2D and organs resistant to its action (type II) of Ca2+ and
is also referred to as hereditary vitamin D–resistant Pi from gut
rickets. Alkaline impaired by
phosphatase deficiency of
TYPE 1 PSEUDOVITAMIN D–DEFICIENT elevated 1,25(OH)2D
RICKETS: RENAL 1α-HYDROXYLASE or resistance
DEFICIENCY to its action

Type 1 pseudovitamin D–deficient rickets is an auto- Ca2+ Pi
somal recessive disorder caused by inactivating muta-
tions in the gene encoding the 1α-hydroxylase enzyme Compensatory PTH promotes
that leads to no or minimal conversion of 25(OH)D to osteoblastic osteoclastic
1,25(OH)2D. Affected children usually present in activity resorption of
the first year of life with hypocalcemia, hypophos- (osteomalacia) bone (Ca2+, Pi ,
phatemia, phosphaturia, normal or increased blood and matrix)
concentrations of 25(OH)D, decreased blood con-
centrations of 1,25(OH)2D, elevated blood con- Widened and irregular Pseudo- Bowing Subperiosteal Cysts and
centrations of alkaline phosphatase, increased blood epiphyseal plate fractures resorption brown tumors
concentrations of parathyroid hormone (PTH), and the Uncalcified
typical signs and symptoms of rickets and osteomalacia osteoid seams
(see Plates 6-18 and 6-21). Additional presenting symp-
toms include motor retardation, muscle weakness, and
growth failure.

The mainstay of therapy for patients with renal
1α-hydroxylase deficiency is lifelong administration of
calcitriol in physiologic doses (e.g., 1 μg/d) with treat-
ment goals of healing the bones and maintaining
normal blood concentrations of calcium, phosphorus,
PTH, creatinine, and alkaline phosphatase. Adequate
calcium supplementation is important, especially during
the bone-healing phase. Overtreatment with calci-
triol—resulting in hypercalcemia, hypercalciuria, and
nephrocalcinosis—should be avoided.

TYPE 2 PSEUDOVITAMIN D–DEFICIENT Rickets or osteomalacia
RICKETS: HEREDITARY VITAMIN
D–RESISTANT RICKETS three- to fivefold above the upper limit of the reference attempt to overcome the receptor resistance should be
range, elevated blood concentrations of alkaline phos- tried in these patients. If high-dose calcitriol is ineffec-
Hereditary vitamin D–resistant rickets is an autosomal phatase, increased blood concentrations of PTH, and tive, long-term, intravenously administered calcium
recessive disorder resulting from mutations in the gene the typical signs and symptoms of rickets and osteoma- infusions should be considered. Treatment effectiveness
encoding the vitamin D receptor, which lead to lacia (see Plates 6-18 and 6-21). The lack of vitamin should be monitored with bone radiographs and meas-
decreased target-organ responsiveness to 1,25(OH)2D. D–receptor activation in keratinocytes causes alopecia urement of blood levels of calcium, phosphorus, PTH,
The clinical presentation depends on the mutations and totalis in some kindreds. creatinine, and alkaline phosphatase. The correct calci-
the amount of residual vitamin D–receptor activity. triol dosage is the dosage that heals the rachitic bone
Affected children usually present in the first 2 years of In addition to oral calcium supplementation, admin- and normalizes the laboratory parameters.
life with hypocalcemia, hypophosphatemia, phosphatu- istration of high-dose calcitriol (e.g., 5–60 μg/d) in an
ria, blood concentrations of 1,25(OH)2D increased

172 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-20 Bone and Calcium

HYPOPHOSPHATEMIC RICKETS Renal phosphate wasting Parathyroid glands PTH normal
generally normal, or elevated
Hypophosphatemic rickets is caused by renal inorganic caused by: may be hyperplastic
phosphate (Pi) wasting, either in isolation or as a com- if disorder has
ponent of a more generalized renal disorder (e.g., Generalized disorder FGF23 mixed etiology
Fanconi syndrome). The usual biochemical profile (e.g., Fanconi syndrome)
includes hypophosphatemia, normal serum calcium Serum and extracellular fluid
concentration, normal serum parathyroid hormone Isolated disorder
(PTH) concentration, and increased blood concentra- X-linked Pi
tion of fibroblast growth factor 23 (FGF23). The most Autosomal dominant PTH further impairs
common hereditary form of hypophosphatemic rickets Autosomal recessive Pi reabsorption
is X-linked followed by autosomal dominant forms Hypercalciuric forms
(associated with activating mutations in the FGF23 Tumor-induced
gene), autosomal recessive forms (associated with inac- osteomalacia
tivating mutations in the dentin matrix protein 1 gene
[DMP1] that result in increased FGF23 expression), and Ca2+ Pi Pi
forms associated with hypercalciuria (e.g., Dent disease). Ca2+ low Ca2+
If the onset of hypophosphatemia is delayed until or normal Pi very
adolescence, the differential diagnosis should include low Absorption
tumor-induced osteomalacia (see following text). because of Pi from
of renal gut does
X-LINKED HYPOPHOSPHATEMIC RICKETS wasting not com-
pensate
The incidence of X-linked hypophosphatemic rickets is Alkaline for loss in
approximately one case per 20,000 live births. Muta- phosphatase urine
tions in the phosphate regulating endopeptidase elevated
homolog on the X chromosome gene (PHEX) are Ca2+ Pi
responsible for this disorder. Although penetrance is
100%, the expression is variable, even in affected indi- Phosphaturia
viduals from the same kindred. PHEX regulates the
degradation and production of FGF23. Excess circulat- Compensatory osteoblastic PTH enhances
ing levels of FGF23 mediate renal phosphate wasting activity (osteomalacia) osteoclastic
by inhibiting phosphate reabsorption by the renal resorption of
sodium–phosphate cotransporter. Children with bone (Ca2+,
X-linked hypophosphatemic rickets usually present Pi , and matrix)
with typical signs and symptoms of osteomalacia
(see Plate 6-21) and retarded linear growth. Additional Pseudofractures Bowing, soft bones
findings unique to X-linked hypophosphatemic
rickets include calcification of ligaments and tendons Flaring Subperiosteal resorption (minimal)
(enthesopathy) and abnormal dentin predisposing to
early tooth decay and tooth abscesses. Typical labora- Widened and irregular
tory findings include low serum concentrations of phos-
phorus and calcitriol (the effects of FGF23 at the renal epiphyseal plate Uncalcified osteoid seams
tubule also impair calcitriol synthesis), increased serum
FGF23 concentration and 24-hour urinary phosphate Rickets or osteomalacia
excretion, normal to increased blood concentrations of
PTH and alkaline phosphatase, and normal blood con- TUMOR-INDUCED OSTEOMALACIA phatemic rickets but who do not have a personal or
centrations of calcium and calcidiol. The diagnosis can family history of the genetic disorder. The main
be confirmed with molecular genetic testing for germ- Tumor-induced osteomalacia is an acquired disorder challenge is to localize the small tumor; it may be a
line mutations in PHEX. caused by small, benign mesenchymal tumors (e.g., small subcutaneous lesion on an extremity or more
sclerosing type of hemangiopericytoma) that hyperse- centrally located. Localization studies usually include
In children, treatment includes orally administered crete FGF23. The clinician should suspect tumor- somatostatin receptor imaging with indium In
phosphate (sodium phosphate or potassium phosphate) induced osteomalacia in patients who present with 111-diethylenetriamine pentaacetic acid-pentetreotide
and calcitriol. Calcitriol therapy is needed to prevent signs, symptoms, and laboratory profiles identical to and total body magnetic resonance imaging. Tumor
the secondary hyperparathyroidism (which can cause those observed in patients with X-linked hypophos- resection corrects all biochemical abnormalities.
further renal phosphate wasting) that occurs with phos-
phate replacement therapy. The goals of therapy in
children are resolution of bone and joint pain and
normal growth. Laboratory parameters that should be
followed during treatment include blood concentra-
tions of phosphorus, calcium, alkaline phosphatase,
creatinine, and PTH and urinary calcium excretion.
Periodic radiographs of the hand and wrist should be
obtained to document bone age and to identify any
recurrence of rickets. In adults, the goals of therapy are
to prevent bone pain and fractures. In patients who are
not closely monitored, hypercalcemia and hypercalciu-
ria may result in calcium–phosphate deposition in the
renal tubules (nephrocalcinosis) and renal tubular
acidosis.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 173

Plate 6-21 Endocrine System

CLINICAL MANIFESTATIONS OF Impaired growth Flaring of metaphyseal ends of tibia and femur.
RICKETS IN CHILDHOOD Craniotabes Growth plates thickened, irregular, cupped, and
axially widened. Zones of provisional
Rickets, a result of chronic hypocalcemia or hypophos- Frontal bossing calcification fuzzy and indistinct. Bone cortices
phatemia, occurs before closure of the epiphyses and Dental defects thinned and medullae rarefied
is usually most evident at sites of rapid bone growth Chronic cough
(e.g., knees, costochondral junctions, distal forearm). Pigeon breast Radiographic findings
Enlargement of the costochondral junctions results in (tunnel chest)
visible nodules—the “rachitic rosary”—and chest wall
deformities (e.g., tunnel chest). The wrist enlarges, and Kyphosis
there is bowing of the distal ulna and radius. Impaired
mineralization causes weak long bones, leading to Rachitic rosary
weight-bearing–dependent skeletal deformities. For Harrison groove
example, whereas an affected infant may have posterior
bowing of the distal tibia, children who can walk may Flaring of ribs
have lateral bowing of the femur and tibia (genu varum). Enlarged ends
In infants, the closure of the fontanelles may be delayed, of long bones
and parietal and frontal bossing and evidence of soft Enlarged abdomen
skull bones (craniotabes) may be present. The “Harri-
son groove” refers to the indentation that results from Coxa vara
the muscular pull of the diaphragmatic attachments to
the lower ribs. Bowleg (genu varum)

The clinical presentation of rickets is dominated by Clinical findings (all or some
skeletal pain, skeletal deformity, fracture, slippage of present in variable degree)
epiphyses, and retarded growth. Hip pain and deform-
ity may result in a waddling or antalgic gait. In patients Radiograph shows variegated rarefaction of pelvic
with hypocalcemic rickets, extraskeletal symptoms may bones, coxa vara, deepened acetabula, and
include decreased muscle tone, proximal myopathy, subtrochanteric pseudofracture of right femur
hypocalcemic seizures, hyperhidrosis, and predisposi-
tion to infections. Radiograph of rachitic hand shows Section of rachitic bone shows sparse, thin
decreased bone density, irregular trabeculae surrounded by much uncalcified
A uniform component of the laboratory profile in trabeculation, and thin cortices osteoid (osteoid seams) and cavities caused
patients with rickets is a marked increase in the blood of metacarpal and proximal by increased resorption
concentration of alkaline phosphatase. The serum phalanges. Note increased axial
calcium concentration is low in patients with hypocal- width of epiphyseal line, especially
cemic rickets and is either normal or slightly depressed in radius and ulna
in those with hypophosphatemic rickets; serum phos-
phorus is low in both hypocalcemic and hypophos- In children with suspected rickets, obtaining thor- and 6-20. Although bone biopsies are usually not
phatemic rickets. The serum parathyroid hormone ough dietary (e.g., calcium and vitamin D) and medica- needed to confirm rickets, they show sparse, thin
(PTH) concentration is above the reference range in tion histories is key. Initial laboratory studies should trabeculae; thick layers of uncalcified osteoid (osteoid
patients with hypocalcemic rickets and is normal in exclude renal failure and hepatic disease. Laboratory seams); and large bone resorption cavities.
those with hypophosphatemic rickets. testing should include measurement of blood
concentrations of calcium, phosphorus, PTH, and Effective treatment of patients with rickets is deter-
Radiographs of the distal ulna usually show findings 25-hydroxyvitamin D. For a description of the typical mined by the underlying cause. Deformities that occur
of impaired mineralization, widening of the epiphyseal laboratory findings in patients with nutritional- before age 4 years usually slowly correct themselves
plates, irregular trabeculation, thin cortices, subperio- deficiency rickets, pseudovitamin D–deficient rickets, with effective therapy. When deformities occur after
steal erosions (caused by the marked secondary hyper- and hypophosphatemic rickets, see Plates 6-18, 6-19, age 4 years (e.g., bowleg, knock-knee), they may be
parathyroidism), and increased axial width of the permanent.
epiphyseal line. Similar findings are evident in radio-
graphs of the knees, which show flaring of the meta-
physeal ends of the tibia and femur and thick and
irregular growth plates. The zones of provisional calci-
fication at the epiphyseal–metaphyseal interface are
fuzzy and indistinct. With advanced rickets, the epiphy-
seal plates become more irregular and cupped. Osteo-
penia is evident in the long bones. Pelvic radiographs
may disclose variegated rarefaction of the pelvic bones,
coxa vara (where the angle between the ball and the
shaft of the femur is reduced to <120 degrees, resulting
in a shortened leg), deepened acetabula, pathologic
fractures, and pseudofractures (Looser zones). Pseu-
dofractures are narrow (2–4 mm) radiolucent lines with
sclerotic borders that are perpendicular to the cortical
bone margin and a few millimeters to several centi-
meters in length. Pseudofractures are frequently bilat-
eral and symmetric and can be seen in the pubic rami,
ischial rami, medial part of the femoral shaft, femoral
neck, outer edge of the scapula, clavicle, ulna, and ribs.
Pseudofractures appear at sites where major arteries
cross the bone and may be caused by the mechanical
forces of normal arterial pulsation on poorly miner-
alized bone (see Plate 6-22).

174 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-22 Bone and Calcium

CLINICAL MANIFESTATIONS OF Thickened
OSTEOMALACIA IN ADULTS and bent
radius and
Osteomalacia is a disorder of impaired mineralization ulna
of newly formed osteoid in adults. Bone is composed of Exostosis
a collagen matrix (osteoid) distributed in a lamellar
pattern and strengthened by pyridinoline crosslinks Supernumerary
between the triple-helical collagen molecules, on which ossicle
alkaline phosphate facilitates the deposition of calcium
and phosphorus to form hydroxyapatite (see Plate 6-3). Circumflex Pseuofracture
Bone remodeling is a continuous process, and new bone scapular (Milkman
formation requires osteoid production from osteoblasts and circumflex syndrome)
followed by mineralization of the osteoid. The miner- humeral
alization step requires an adequate supply of calcium arteries
and phosphorus in extracellular fluid and normal bio- in relation
activity of alkaline phosphatase. Hypophosphatemia is to bones
the most common cause of osteomalacia (see Plate
6-20). Hypophosphatasia, a rare inherited disorder, is Clavicle Scapula
associated with low concentrations of alkaline phos-
phatase in serum and bone that cause defective bone can be performed. Tetracyclines are fluorescent; they bands of deposited tetracycline. Normal bone growth
and tooth mineralization, resulting in osteomalacia and are deposited in a band at the mineralization front and rate is 1 μm per day. In patients with osteomalacia, the
severe periodontal disease (see Plate 6-27). are easily seen with a fluorescence microscope. A tetra- bone growth rate is slow, and there are large amounts
cycline is administered for 3 days, and the dosing is of unmineralized osteoid.
The clinical presentation of osteomalacia ranges repeated 11 to 14 days later. An iliac crest bone biopsy
from incidental detection of osteopenia on radiographs is performed 3 to 5 days after the second tetracycline The treatment of osteomalacia is guided by the
to markedly symptomatic patients with diffuse bone course is completed. The bone growth rate can be esti- underlying cause. For example, patients with vitamin D
pain (most prominent in the pelvis, lower extremities, mated on the basis of the distance between the two deficiency should be treated with vitamin D and calcium
and lower spine), proximal muscle weakness, muscle supplementation.
wasting, hypotonia, and waddling gait. Low-impact
fractures of the ribs and vertebral bodies may also be
the initial presentation.

Radiographs typically show osteopenia with thinning
of the cortex and loss of vertebral body trabeculae.
With advanced vertebral body softening, end-plate
concavities develop (“codfish” deformities) (see Plate
6-17). Looser zones (pseudofractures) are narrow
(2–4 mm) radiolucent lines with sclerotic borders that
are perpendicular to the cortical bone margin and a few
millimeters to several centimeters in length. Pseudo-
fractures are frequently bilateral and symmetric and can
be seen in the pubic rami, ischial rami, medial part of
the femoral shaft, femoral neck, outer edge of the
scapula, clavicle, ulna, and ribs. Pseudofractures appear
at sites where major arteries cross the bone and may be
caused by the mechanical forces of normal arterial pul-
sation on poorly mineralized bone. Pseudofractures
appear as hot spots on bone scintigraphy. Because
Milkman initially recognized pseudofractures in 1930,
the term Milkman syndrome has been used when a
patient with osteomalacia has multiple, bilateral, sym-
metric pseudofractures. If secondary hyperparathy-
roidism is present, additional radiographic findings may
be evident (e.g., subperiosteal resorption, bone cysts).
With severe and long-standing osteomalacia, bowing of
the tibia, radius, and ulna, as well as coxa profunda hip
deformities, may occur.

The findings on laboratory testing in adults
with osteomalacia depend on the underlying patho-
physiology. For example, the typical laboratory
profile in patients with osteomalacia caused by nutri-
tional vitamin D deficiency includes hypocalcemia,
hypophosphatemia, low blood concentration of
25-hydroxyvitamin D, and increased blood concentra-
tion of parathyroid hormone (see Plate 6-18).

If there is doubt about the diagnosis of osteomalacia,
a bone biopsy using double labeling with tetracycline

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 175

Plate 6-23 Endocrine System

Manifestations of advanced, diffuse Paget disease of bone (may occur singly or in combination)
Enlarged head, headache

Deafness due to compression of nerve
in bony meatus

Kyphosis Increased cardiac output due to great
bone vascularity (may progress to
PAGET DISEASE OF THE BONE high-output failure)

Paget disease of the bone (osteitis deformans) is a Bone pain, most commonly in back
localized skeletal disorder of uncontrolled, highly or hips; radicular pain with spine
active, large osteoclasts that results in increased bone involvement
resorption, which triggers intense and chaotic osteob-
lastic bone formation. Increased local bone blood flow Bowing of limbs
is observed, and fibrous tissue develops in the adjacent
bone marrow. The new bone lacks the usual lamellar Increased warmth and tenderness over bones;
structure and is disorganized. This disorder affects increased limb volume
approximately 3% of adults older than 40 years; it is
usually asymptomatic and evolves slowly. Mild cases often asymptomatic (may be discovered incidentally on radiographs taken for other reasons)

Although the prevalence of Paget disease is the same Lateral radiograph shows Extremely thickened Characteristic radio- Healing chalk-stick
in men and women, it is more commonly symptomatic patchy density of skull, skull bones, which graphic findings in tibia fracture
in men. The typical age at the time of detection is in with areas of osteopenia may encroach on include thickening,
the sixth decade of life. The method of detection is (osteoporosis nerve foramina or bowing, and coarse
frequently incidental (e.g., increased serum alkaline circumscripta cranii) brainstem and cause trabeculation, with
phosphatase observed on routine blood testing or evi- hydrocephalus (shown) advancing radiolucent
dence seen on a radiograph done for other reasons). by compressing wedge
When symptomatic, the primary symptom is pain cerebral aqueduct
caused by periosteal stretching or microfractures. The
bone pain is aggravated by weight bearing. The skin
may be warm over pagetic bone because of the increased
blood flow. Paget disease can affect one bone (monos-
totic) or multiple bones (polyostotic). The most
common bones to be involved are the pelvis, spine,
femur, skull, and tibia. With femur or tibia involve-
ment, bowing of the legs is common. The bowing
deformities in the bones of the lower extremities lead
to gait changes. Transverse traumatic and pathologic
bone fractures are common complications.

Spine involvement can lead to kyphosis and symp-
toms related to spinal cord compression. Hearing loss
(caused by compression of the eighth cranial nerve or
pagetic involvement of the middle ear ossicles) and skull
deformities (frontal and occipital areas) are common
when the skull is involved. Compression of the second,
fifth, and seventh cranial nerves in the skull may result
in visual symptoms and facial palsy. Skull base involve-
ment predisposes to platybasia (invagination of the skull
by cervical vertebral bodies) and hydrocephalus by
compression of the cerebral aqueduct.

Other complications of Paget disease may develop
over time. Bony neoplasia (giant cell tumors [osteoclas-
tomas], fibrosarcomas, chondrosarcomas, and osteosar-
coma) occurs more frequently in patients with Paget
disease. Primary hyperparathyroidism is also more
common. The increased blood flow to bone (when
more than 20% of the skeleton is involved) can lead to
high-output heart failure.

EVALUATION of the increased risk of primary hyperparathyroidism, of the rate of synthesis of osteocalcin by osteoblasts),
serum calcium should be measured. If the imaging and C-terminal and N-terminal propeptides of type
A thorough history and physical examination are studies cannot distinguish between Paget disease and I collagen (reflecting changes in synthesis of new
important. A radionuclide bone scan can be helpful in metastatic neoplasm, a bone biopsy may be needed. collagen). Bone resorption can be followed by measur-
identifying the sites of involved bone; areas of pagetic On bone biopsy, an irregular marble bone–type pattern ing urinary excretion of hydroxyproline (reflecting
bone appear as focal areas of increased uptake. Plain and giant osteoclasts are seen. Measurement of bone breakdown of collagen in bone) and the collagen N-
radiographs should be obtained of all the sites identified markers at baseline and with treatment is useful. telopeptide and C-telopeptide crosslinks. Both the
on the bone scan to confirm Paget disease and its Markers of bone formation include blood concentra- resorption and synthetic markers are increased in
extent. For patients with skull involvement, baseline tions of bone-specific alkaline phosphatase (reflecting patients with untreated Paget disease and normalize
and annual audiograms should be performed. Because cellular activity of osteoblasts), osteocalcin (an estimate with effective treatment.

176 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-24 Bone and Calcium

Hyperparathyroidism may Renal tubule
coexist or be related

Serum and extracellular fluid Ca2+
Pi
PATHOGENESIS AND TREATMENT Ca2+ Ca2+ Pi
OF PAGET DISEASE OF THE BONE Pi Hydroxyproline
NTX
The cause of Paget disease may be a viral trigger super- Gut Serum Ca2+ and P usually normal CTX
imposed on a genetic predisposition. Viral inclusions
are common in the pagetic osteoclasts and are absent Ca2+ and Pi BSAP
in normal osteoclasts. Approximately 30% of patients absorption P1NP
with Paget disease have a family history of this disorder. normal Osteocalcin
The understanding of this genetic predisposition is
evolving; mutations in the ubiquitin-associated domain Ca2+ Ca2+
of the gene encoding sequestosome 1 (SQSTM1) have Pi Pi
been found in patients with familial and sporadic Paget
disease. Likely a consequence of Paget disease, primary Osteoclastic resorption of
hyperparathyroidism is also more common in affected bone and osteoblastic
patients. deposition of bone greatly
increased
Most patients with Paget disease are asymptomatic
and do not require treatment. The main indications for Hydroxyproline
treatment are to ameliorate symptoms (e.g., bone pain, NTX
nerve compression) and to prevent complications. CTX
Treatment should be considered in asymptomatic
patients who have moderately active disease (e.g., serum Abnormal bone structure, coarse trabeculation, thickening,
alkaline phosphatase concentration higher than three- bowing, pseudofractures, fractures, hypervascularity
fold above the upper limit of the reference range), sites
of disease that can predispose to complications (e.g., NN
major weight-bearing bones, joints), or extensive skull
involvement. Also, early treatment in young patients C
should be considered with a goal of preventing more N
advanced disease. C

The key to treatment is to suppress osteoclastic activ- C
ity. In the past, the cornerstones of pharmacologic
therapy were calcitonin and plicamycin. However, Section of bone shows intense osteoclastic Electron-microscopic view of multinucleated
bisphosphonates specifically inhibit osteoclast activity and osteoblastic activity and mosaic osteoclast with nuclear inclusions that may
and are the treatment of choice. Bisphosphonates (e.g., of lamellar bone be viruses (arrows). C = cytoplasm; N = nuclei
etidronate, pamidronate, alendronate, tiludronate, rise-
dronate, and zoledronic acid) are long-acting pyrophos- N-terminal propeptides of type I collagen (P1NP) Bone markers can be periodically measured every 2
phate analogues that are poorly absorbed from the (reflecting changes in synthesis of new collagen). Bone to 6 months after a single intravenous infusion of a
gastrointestinal tract. They are given either in large oral resorption can be followed by measuring urinary excre- bisphosphonate, and when they start to rise above the
doses or intravenously. For example, in patients with tion of hydroxyproline (reflecting breakdown of colla- reference range, an additional infusion can be consid-
mild disease, a single dose of intravenous pamidronate gen in bone) and the collagen crosslinks N-telopeptide ered. A similar strategy with oral bisphosphonates can
or zoledronic acid may maintain a biochemical remis- (NTX) and the C-telopeptide crosslink (CTX). Both be used: treatment with an oral agent for 4 to 6 months
sion for 12 to 18 months. The main adverse effect of the resorption and synthetic markers are increased in or until the bone markers normalize, then treatment
intravenous bisphosphonates is a flulike symptom patients with untreated Paget disease and normalize reinitiation when the bone markers become abnormal
complex in 20% of patients that lasts for 1 or 2 days with effective treatment. again.
after the infusion. With oral bisphosphonates, the main
adverse effect is esophageal irritation; thus, they should
be taken in the fasting state with 240 mL of water, and
patients should remain in the upright position for at
least 30 minutes. Oral bisphosphonates are adminis-
tered for 4 to 6 months or until the bone markers
normalize. Because bisphosphonates can lower the
serum calcium level and cause secondary hyperparathy-
roidism, all patients should take optimal oral calcium
and vitamin D supplementation. Adequate vitamin D
repletion should be documented with measurement of
the serum 25-hydroxyvitamin D concentration.

Measurement of bone resorption and formation
markers at baseline and with treatment is useful. With
bisphosphonate treatment, resorption markers decrease
first followed by bone formation markers. Markers of
bone formation include blood concentrations of bone-
specific alkaline phosphatase (BSAP) (reflecting cellular
activity of osteoblasts), osteocalcin (an estimate of the
rate of synthesis of osteocalcin by osteoblasts), and

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 177

Plate 6-25 Endocrine System
MODERATE TO SEVERE OSTEOGENESIS IMPERFECTA TYPES III, IV, V, VI, VII, AND VIII

Sclerae white to blue
Teeth opalescent

Deformity severe

Triangular facies

Shortening severe

OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta (OI), frequently referred to as Sclerae normal to blue
“brittle bone disease,” is a rare (one per 200,000 live
births) hereditary connective tissue disorder with a vari- Teeth usually opalescent
able clinical presentation. Moderate to severe OI is
evident in infancy with bone fractures associated with Limb deformity severe
little or no trauma; mild OI may not become clinically Locomotion severely limited
evident until adulthood when affected individuals
present with premature osteoporosis. Radiograph shows severe Radiograph shows very
scoliosis and chest deformity thin and osteoporotic
Approximately 90% of individuals with OI have bones; fracture rate high
autosomal dominant germline mutations in the genes
encoding the proteins that form type I collagen joints at the wrists, hands, and feet may be evident. mineralization defect,” is associated with an accumula-
(COL1A1 and COL1A2). Both normal structure and Patients with OI types IV, V, VI, VII, or VIII can have tion of osteoid in bone tissue and a fish-scale pattern of
normal amount of type I collagen are necessary for normal sclerae. Type III is a progressive deforming bone lamellation. Type VII OI, previously termed
normal bones, sclerae, tendons, ligaments, teeth, and form of OI that eventuates in the use of a wheelchair. “congenital brittle bones with rhizomelia,” is recessive
skin. Mutations in other collagen-related genes have Type IV OI is associated with less growth retardation in inheritance and has been identified in only one
been found in a minority of patients with OI. For than type III. Type V OI, previously termed “congenital kindred. Type VIII OI is recessive in inheritance and
example, germline mutations in the gene encoding the brittle bones with redundant callus formation,” is is associated with prolyl 3-hydroxylase 1 deficiency,
cartilage-associated protein—important for the post- not associated with dentinogenesis imperfecta. Type VI resulting in undermineralized ribs and long bones and
translational modification of collagen types I and II— OI, previously termed “congenital brittle bones with matrix disorganization.
have been documented in some patients with OI.
Affected individuals in the same family may have
markedly different disease severity, implicating other
genetic or environmental factors that affect the patho-
genesis of OI.

The key clinical features of OI include recurrent
bone fractures, blue sclerae, opalescent teeth (dentino-
genesis imperfecta with fragile and discolored teeth),
easy bruising, basilar skull deformities, hearing loss, and
increased ligament laxity. OI can be classified clinically
on the basis of disease severity.

Type I OI (mild OI) is associated with mild manifes-
tations, including infrequent bone fractures (primarily
long bones and ribs), normal stature, premature oste-
oporosis, mild scoliosis, blue sclerae, teeth that appear
normal or opalescent, and premature hearing loss.
Locomotion is usually normal. Type I OI is usually
caused by a deletion of one allele of the COL1A1 pro-
collagen gene, resulting in normal collagen structure
but decreased production.

Type II OI (lethal perinatal OI), characterized by
multiple severe fractures and respiratory failure, leads
to death in utero or shortly after birth.

OI types III, IV, V, VI, VII, and VIII are associated
with severe bone fragility. Children present with fre-
quent fractures and severe limb deformities. Fractures
can even include the ossicles of the ear, resulting in
conductive hearing loss. Kyphoscoliosis and short
stature are typical of moderate to severe OI. Locomo-
tion is usually severely limited. Hypermobility of the

178 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 6-26 Bone and Calcium

MILD OSTEOGENESIS IMPERFECTA TYPE I

Deafness in adulthood Sclerae blue

Teeth normal or opalescent

OSTEOGENESIS IMPERFECTA Scoliosis mild

(Continued)

All laboratory parameters can be normal in patients Deformity moderate
with OI. Hypercalciuria may be present, and it corre-
lates with the severity of bone disease (increased life- Shortening mild
long risk of fractures and shorter stature). In patients
with more severe disease, bone marker measurement Sclerae usually blue Teeth normal or opalescent
may be abnormal. Decreased levels of bone formation
markers may be found. For example, the blood concen- Radiograph shows thin and Radiograph shows mild scoliosis
trations of the following bone formation markers may osteoporotic bones (variable).
be low: bone-specific alkaline phosphatase (reflecting Fracture rate moderate; Locomotion normal or with crutch
cellular activity of osteoblasts), osteocalcin (an estimate deformity mild, often
of the rate of synthesis of osteocalcin by osteoblasts), amenable to intramedullary
and the C-terminal and N-terminal propeptides of type fixation
I collagen (reflecting changes in synthesis of new col-
lagen). Bone resorption markers that may be increased skeletal radiographs, pulmonary function, and hearing bone turnover and results in improved BMD, decreased
above the upper limit of the reference range are urinary loss. Patients with OI type III should also have periodic number of fractures, and improved mobility. Treat-
excretion of hydroxyproline (reflecting breakdown of echocardiograms to assess for aortic valve insufficiency ment options under investigation include growth
collagen in bone) and collagen crosslinks (N- caused by aortic root dilation. Nerve compression syn- hormone, bone marrow transplantation, and gene
telopeptide crosslinks and the C-telopeptide crosslink). dromes may develop with basilar skull deformities. therapy.

A bone biopsy is usually not needed to confirm the Pharmacologic therapy with a bisphosphonate agent Individuals with type I OI have a normal life expect-
diagnosis. However, if performed, bone histology should be considered in patients with any form of OI ancy. Individuals with moderately severe OI may have
shows disorganized bone, increased bone turnover, unless there is a mineralization defect (e.g., type VI OI). a shortened lifespan related to thoracic deformities and
decreased cortical width, decreased trabecular number Bisphosphonate therapy inhibits bone resorption and immobility.
and width, and decreased cancellous bone volume.

The diagnosis of OI is based on the presentation of
increased bone fragility, positive family history of
bone fragility, blue sclerae, dentinogenesis imperfecta,
hearing loss, and molecular genetic testing for muta-
tions in COL1A1 and COL1A2. In addition to OI, the
differential diagnosis of frequent bone fractures in
childhood includes rickets and child abuse. Less
common disorders to consider include idiopathic juve-
nile osteoporosis (nonhereditary form of isolated and
transient childhood osteoporosis), hypophosphatasia
(autosomal recessive disorder caused by a deficiency
of tissue nonspecific alkaline phosphatase; see Plate
6-27), juvenile Paget disease (autosomal recessive dis-
order), polyostotic fibrous dysplasia (McCune-Albright
syndrome) with bony cystic or ground glass lesions,
Ehlers-Danlos syndrome (caused by a deficiency in the
collagen crosslinking enzyme lysyl oxidase), Menkes
disease (copper deficiency that impairs the function of
the collagen crosslinking enzyme lysyl oxidase), and
Cole-Carpenter syndrome (osteoporosis, craniosynos-
tosis, hydrocephalus, proptosis, and short stature).

TREATMENT

A multidisciplinary team—including specialists in
genetics, orthopedics, neurology, physical therapy,
occupational therapy, dental care, otolaryngology,
psychology, and endocrinology—is needed for effective
treatment of symptoms and complications related
to OI. Treatment goals include decreasing bone
fracture incidence, enhancing mobility, preventing
bone deformities and scoliosis, and managing pain
effectively.

Patients with OI should be evaluated regularly for
bone mineral density (BMD), fractures detected on

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 179

Plate 6-27 Endocrine System

Serum and extracellular fluid

Elevated intracranial Serum Pi Pyrophosphate (PPi),
pressure due to normal Phosphoethanolamine,
craniosynostosis Phosphoserine,
Phosphorylcholine,
Pneumonia Pyridoxal 5-phosphate
related to
chest Serum alkaline Serum Ca2+ normal or
deformity phosphatase elevated because
activity very
low or absent not deposited
in bone
Hypercalciuria,
nephrocalcinosis, Rachitic
defor-
renal failure
mities

Infantile form

(most serious, often fatal)

HYPOPHOSPHATASIA Alkaline

Hypophosphatasia, a rare inherited disorder, is associ- phosphatase, Urine
ated with low concentrations of alkaline phosphatase in Osteoblasts Calcium
serum and bone that cause defective bone and tooth which normally
mineralization, resulting in osteomalacia and severe elevated
periodontal disease. Hypophosphatasia results from promotes bone
mutations in the alkaline phosphatase gene (ALPL) that
encodes the tissue-nonspecific isoenzyme of alkaline Early loss of mineralization
phosphatase. Perinatal and infantile forms are inherited
in an autosomal recessive manner, and milder forms by hydrolyzing
that present later in life can be either autosomal domi- deciduous teeth PPi, is absent,
nant or autosomal recessive, depending on the specific deficient, or Collagen Noncollagenous Inorganic
gene mutation(s). proteins and pyrophosphate
ineffective in proteoglycans Uncalcified greatly elevated
The perinatal lethal form, with an estimated preva- Characteristic hypophos-
lence of one in 100,000, results from complete absence rachitic phatasia PPi Ca++ matrix Phospho-
of alkaline phosphatase. Perinatal lethal hypophos- deformities
phatasia causes lack of mineralized bone in utero, severe Pyrophosphate ethanolamine
deformities with skin-covered osteochondral spurs pro- greatly elevated
truding from the legs and forearms, rachitic deformities (PPi) inhibits
of the chest, hypoplastic lungs, premature craniosynos- bone Mineralized
tosis with secondary increased intracranial pressure,
seizures, hypercalcemia, nephrocalcinosis, and renal mineralization bone Phosphoserine
failure.
Childhood form (less greatly elevated
Milder ALPL mutations, characterized by autosomal serious than infantile form)
dominant transmission and variable expressivity, are
associated with presentation during childhood or in Premature M
adulthood with early loss of teeth and osteomalacia. loss of teeth O
Childhood hypophosphatasia presents with skeletal
deformities (e.g., enlarged joints), focal defects at the OC
end of long bones, short stature, and premature loss of
teeth. The bone disease may seem to spontaneously MO
resolve, only to reappear in adulthood. Individuals with
the adult form of hypophosphatasia usually become Osteomalacia, Section of trabecular bone from patient
symptomatic in the fourth or fifth decades of life. Pre- pseudofractures, with infantile hypophosphatasia shows
senting symptoms include thigh pain caused by femoral true fractures very broad seams of uncalcified matrix
pseudofractures, metatarsal stress fractures, chondro- (stained red) overlying thin trabeculae
calcinosis, and odontohypophosphatasia (severe dental Adult form of mineralized bone (stained blue).
caries, loose teeth on dental examination, and prema- (least serious but M = marrow; O = osteoblasts;
ture exfoliation of primary teeth [especially incisors]). clinically heterogeneous) OC = osteoclasts. (Outlined panel
is area shown in enlargement.)
Alkaline phosphatases catalyze the hydrolysis of
phosphomonoesters with release of inorganic phospho- Hypophosphatasia can be confirmed by finding mutations, nonsense mutations, or small insertions.
rus. At the osteoblast cell surface, tissue-nonspecific increased blood and urine concentrations of organic The array of different mutations is responsible in part
isoenzyme of alkaline phosphatase generates inorganic phosphate compounds (e.g., phosphoethanolamine, for the variable clinical expression; in other words,
phosphate that is needed for hydroxyapatite crystalliza- phosphorylcholine, and pyridoxal 5-phosphate). Find- patients with severe disease have ALPL mutations that
tion. In addition, the buildup of pyrophosphate inhibits ings on bone biopsy are indistinguishable from findings result in no enzyme activity, and patients with mild
bone mineralization. of other forms of rickets. In adults, blood concentra- disease have ALPL mutations that result in some
tions of calcium and phosphorus are normal. tissue-nonspecific isoenzyme of alkaline phosphatase
Hypophosphatasia should be suspected when the activity.
blood concentration of total alkaline phosphatase is Genetic testing is a key step to confirm the diagnosis
below the reference range. Blood total alkaline phos- of hypophosphatasia. Most mutations in the ALPL gene Treatment is directed at signs and symptoms. To
phatase concentrations may be decreased in other set- are missense mutations; the rest are deletions, splice site date, there is no curative treatment.
tings (e.g., early pregnancy, anemia, or hypothyroidism).

180 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 7

LIPIDS AND NUTRITION

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Plate 7-1 Lipids and Nutrition
Utilization

Cholesterol
synthesis

CHOLESTEROL SYNTHESIS AND Physical activity
METABOLISM
VLDL/LDL/HDL Peripheral tissue

Cholesterol is a 4-ring hydrocarbon structure with an Inheritance Bile acids Enterohepatic Chylomicron
8-carbon side chain. Cholesterol serves as a key com- recirculation remnant
ponent of cell membranes, and it is the substrate for
synthesis of steroid hormones and bile acids. Choles- Interaction of factors affecting
terol is either synthesized endogenously or obtained serum cholesterol levels
exogenously by ingestion of animal fats (e.g., meat,
eggs, and dairy products). The biosynthesis of choles- Dietary fat and cholesterol Chylomicron
terol starts with three molecules of acetate that are
condensed to form 3-hydroxy-3-methylglutaryl coen- Lipoprotein structure
zyme A (HMG-CoA). HMG-CoA is then converted to
mevalonic acid by HMG-CoA reductase—the rate- apo C (I, II, III) apo B100 apo C
limiting step in cholesterol biosynthesis—and meval- (I, II, III)
onic acid is converted to cholesterol. Competitive Polar shell apo E
inhibitors of HMG-CoA reductase (statins) are used Free cholesterol
clinically to decrease cholesterol biosynthesis and to Phospholipid apo E
lower serum cholesterol concentrations. Very low-density lipoprotein (VLDL)
Nonpolar core
Cholesterol is metabolized by the biliary excretion Cholesterol ester
of free cholesterol or by conversion to bile acids that Triglyceride
are secreted into the intestine. Approximately 50% of
biliary cholesterol and 97% of bile acids are reabsorbed apo B48
in the small intestine and recirculate to the liver (enter-
ohepatic circulation); the remaining biliary cholesterol apo A (I, II, IV) apo B100
and bile acids are excreted in the feces.
Chylomicron Low-density lipoprotein (LDL)
Lipoproteins, which are composed of protein, trig-
lycerides, cholesterol esters, and free cholesterol, are Cholesterol is transported in blood as macromolecules of apo A (I, II)
macromolecules that transport cholesterol and triglyc- lipoproteins, with the nonpolar lipid core surrounded by
erides in the blood to target tissues (for bile acid for- a polar monolayer of phospholipids and the polar portion
mation, adrenal and gonadal steroidogenesis, energy of cholesterol and apolipoproteins. Specific lipoproteins
production). The 12 proteins in the lipoproteins are differ in lipid core content, proportion of lipids in the core,
termed apolipoproteins (apo) and are given letter designa- and proteins on the surface. Lipoproteins are classified
tions. The apolipoproteins act as ligands for receptors by density as chylomicrons, very low-density lipoproteins
and as cofactors for enzymes. The lipoproteins have a (VLDLs), low-density lipoproteins (LDLs), and high-density
nonpolar lipid core surrounded by a polar monolayer lipoproteins (HDLs).
of phospholipids and the polar portions of cholesterol
and apolipoproteins. Specific lipoproteins differ in the apo E apo C (I, II, III)
lipid core content, the proportion of lipids in the core,
and the protein on the surface. Lipoproteins are classi- High-density lipoprotein (HDL)
fied on the basis of density as chylomicrons, very low-
density lipoprotein (VLDL), low-density lipoprotein lipoprotein lipase (LPL) and LCAT. Apo B100 is a struc- isoform (homozygous) results in less efficient clearance
(LDL), and high-density lipoprotein (HDL). tural protein for VLDL and LDL and serves as a ligand of chylomicrons and VLDL and is clinically referred to
for the LDL receptor. Apo B48 is critical for the forma- as familial dysbetalipoproteinemia (see Plate 7-9).
• Chylomicrons are large, low-density particles that tion and secretion of chylomicrons. Apo CI serves to
transport dietary lipid (see Plate 7-2).The associ- activate LCAT. Apo CII is a key cofactor for LPL. Apo The cholesterol concentration in the blood is con-
ated apolipoproteins include apo A (I, II, IV); apo CIII inhibits the hydrolysis of triglycerides by LPL. trolled by the LDL receptor. The LDL receptor medi-
B48; apo C (I, II, III), and apo E. The three genetically determined isoforms of apo E ates the endocytosis of apo B– and apo E–containing
clear lipoproteins (VLDL and chylomicrons) from the lipoproteins (LDL, chylomicron remnants, VLDL, and
• VLDL transports primarily triglycerides. The circulation by serving as ligands for the VLDL remnant VLDL remnants) into cells. The number of LDL
associated apolipoproteins include apo B100, apo C receptor. The presence of two copies of the apo E2 receptors on the cell surface is regulated to maintain
(I, II, III), and apo E. normal intracellular cholesterol content.

• LDL transports primarily cholesterol esters and is
associated with apo B100.

• HDL also transports cholesterol esters. HDL is
associated with apo A (I, II), apo C (I, II, III), and
apo E.

How lipids are transported and metabolized is deter-
mined in large part by the apolipoproteins. For example,
apo AI is not only a structural protein in HDL, but it
also activates lecithin–cholesterol acyltransferase
(LCAT). Apo AII is a structural protein of HDL and
activates hepatic lipase. Apo AIV is an activator for

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 183

Plate 7-2 Endocrine System

Pancreas
Bile Pancreatic juice

cCySshetocorkleeint-iinn

Intestinal wall Glycocalyx
Pancreatic Intestinal
lipase Hydrolysis
lipase (partial or
complete)
Micelles
Emulsion

GASTROINTESTINAL ABSORPTION To liver To systemic
OF CHOLESTEROL AND circulation via
TRIGLYCERIDES thoracic duct

Dietary fat digestion starts in the stomach and is com- Lymphatics
pleted in the small intestine. Most dietary lipid is in the
form of long-chain triglycerides (three fatty acids [with Portal
at least 12 carbon atoms each] that are esterified to vein
glycerol). Other dietary lipids include phospholipids,
plant sterols, cholesterol, and fat-soluble vitamins (vita- Chylomicron
mins A, D, E, and K). Gastric peristalsis and mixing
serve to disperse dietary triglycerides and phospholipids Epithelial cell Microvilli
into an emulsion. Intestinal (gastric) lipase acts on the
oil droplets in the emulsion to generate free fatty acids KEY Cholesterol Cholesterol esters
and diglycerides. The presence of fatty acids in the Triglycerides (long and short chain) Carotene Glycerol
small intestine leads to the secretion of cholecystokinin. Diglycerides (long and short chain) Naϩ, Kϩ
Cholecystokinin promotes the secretion and release Monoglycerides (long and short chain) Mg2ϩ, Ca2ϩ
of pancreatic enzymes into the intestinal lumen (see Fatty acids (long and short chain) Soluble Insoluble
Plate 5-2); it also promotes contraction of the gall-
bladder, leading to release of concentrated bile. The mesenteric lymphatic system that flows to the thoracic lipoprotein lipase activity increases in heart muscle and
pancreatic lipase metabolizes triglycerides to fatty duct, where they enter the systemic circulation. Chy- decreases in adipose tissue. In addition, in the postpar-
acids and monoglycerides. Another pancreatic enzyme lomicrons are therefore present in postprandial plasma tum state, breast lipoprotein lipase activity increases
is phospholipase A2, which breaks down dietary but are absent with fasting. Apo CII is a cofactor for 10-fold to promote milk production. Because of the
phospholipids. lipoprotein lipase, the enzyme that hydrolyzes the core action of lipoprotein lipase, the circulating chylomi-
triglycerides of the chylomicron and releases free fatty crons become progressively smaller, and triglyceride-
By partially solubilizing water-insoluble lipids, bile acids. Lipoprotein lipase is bound to the capillary poor chylomicron remnants are removed from the
salt micelles facilitate intestinal transport of lipids to the endothelial cells in muscle, adipose, and breast tissues. circulation in the liver, where apo E is the ligand for
intestinal epithelial cells (enterocytes) for absorption. The activity of lipoprotein lipase is regulated based the hepatic low-density lipoprotein receptor–related
Specific carrier proteins facilitate diffusion of lipids on energy needs. For example, in the fasting state, protein.
across the brush border membrane. In addition, ente-
rocytes in the duodenum and proximal jejunum directly
take up long-chain fatty acids by passive transfer.
Medium-chain fatty acids (six to 12 carbon atoms) are
not esterified, and the enterocytes release these directly
into the portal venous system along with other absorbed
nutrients. Long-chain fatty acids and monoglycerides
are re-esterified into triglyceride in the smooth endo-
plasmic reticulum of the enterocyte. In addition, cho-
lesterol is esterified by cholesterol acyltransferase. The
reassembled lipids are coated with apolipoproteins
(apo) (see Plate 7-1) to produce chylomicrons in the
Golgi apparatus. The primary intestinal apolipopro-
teins are apo B48, apo AI, and apo AIV. Chylomicrons
acquire apo C and apo E during transit in the lymph
and blood. Approximately 85% of the chylomicron is
composed of triglyceride. The chylomicrons are too
large to cross intercellular junctions linking to capillary
epithelial cells. Thus, chylomicrons are transported
across the basolateral membrane by exocytosis into the

184 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-3 Lipids and Nutrition

REGULATION OF LOW-DENSITY Hepatic uptake LDL apo B100 Intracellular cholesterol content and LDL receptor
LIPOPROTEIN RECEPTOR AND of cholesterol-rich synthesis tightly regulated by cells’ need for cholesterol.
CHOLESTEROL CONTENT LDL regulated by Sterol regulatory element–binding protein (SREBP)
availability of mediates LDL receptor synthesis. LDL receptors
The cholesterol concentration in the blood is control- LDL receptors regulate cholesterol uptake via LDL. Modulation
led primarily by the low-density lipoprotein (LDL) to interact with of HMG-CoA reductase activity regulates cholesterol
pathway. Approximately 70% of total plasma choles- apo B100 synthesis. High cholesterol levels in liver lead to
terol is LDL. The LDL receptor—located on the increased storage of cholesterol ester.
surface of all cells—facilitates the internalization of
lipoproteins. Approximately 75% of LDL is taken up Coated
by hepatocytes. The number of LDL receptors on each pit
cell is in flux and is tightly regulated to keep the intra-
cellular cholesterol concentration constant. Sterol reg- Hepatic cell
ulatory element–binding protein (SREBP) mediates
LDL receptor synthesis. Thus, when a cell’s cholesterol LDL receptor LDL receptor
content is in positive balance, LDL receptor expression recycled synthesized and
is downregulated by decreased expression of SREBP. transported
In addition, with increased cellular cholesterol, the cho- LDL to cell surface
lesterol synthetic enzyme 3-hydroxy-3-methylglutaryl receptor
coenzyme A (HMG-CoA) reductase is also downregu-
lated. When a cell’s cholesterol content is in negative Recycling Golgi
balance, increased expression of SREBP leads to vesicle
increased numbers of LDL receptors and enhanced LDL receptor
cholesterol uptake from the circulation. Coated
vesicle Endoplasmic
The LDL receptor binds lipoproteins that contain reticulum
the apolipoproteins (apo) apo B100 and apo E (e.g., Increased
LDL, chylomicron remnants, very low-density lipopro- Bile acids intracellular
tein [VLDL], and VLDL remnants). The lipoprotein– cholesterol
LDL receptor complex localizes to an area of the cell decreases Nucleus
membrane referred to as the “coated pit.” The coated HMG-CoA
pit contains clathrin that facilitates the clustering of Endosome reductase HMG-CoA Decreased
LDL receptors to an area of the cell membrane that can activity, reductase synthesis
invaginate to form an intracellular vesicle (endosome). LDL cholesterol diminishing of LDL
As the endosome becomes more acidic, the LDL recep- esters and cholesterol receptor
tor and lipoprotein dissociate and the lipoproteins are amino acids synthesis RNA
degraded in lysosomes. The free LDL receptor returns degraded
to the cell surface in a recycling vesicle. The intracel- Cholesterol
lular pool of cholesterol and cholesterol esters in the Amino
hepatocyte is dynamic. Increased intracellular choles- acids SREBP
terol enhances acyl-CoA:cholesterol acyltransferase Lysosome
(ACAT) activity, increasing the esterification and ACAT
storage of cholesterol. In turn, cholesterol ester hydro- Cholesterol excretion
lase can generate free cholesterol. via bile acids Cholesterol Increased cholesterol in
ester storage intracellular membranes
The guidelines from the 2002 National Cholesterol Increased intracellular droplet inhibits SREBP, decreasing
Education Program suggest the following cutoffs for cholesterol enhances LDL receptor synthesis
plasma total cholesterol concentrations: less than ACAT activity, increasing
200 mg/dL, desirable; between 200 and 240 mg/dL, storage of cholesterol ester
borderline high; and greater than 240 mg/dL, high.
Increased blood concentrations of cholesterol are Type III hyperlipoproteinemia (familial dysbetalipo- structural similarity to plasminogen and can interfere
related to increased production or secretion into the proteinemia) is an autosomal recessive disorder charac- with fibrinolysis. Increased plasma Lp(a) is associated
circulation or to decreased clearance or removal from terized by moderate to severe hypercholesterolemia and with increased CHD risk.
the circulation (or both). hypertriglyceridemia and is the result of mutations in
the gene encoding apo E, with resultant defective lipo- Polygenic hypercholesterolemia refers to combina-
Familial hypercholesterolemia (FH) is an autosomal protein binding to the LDL receptor (see Plate 7-9). tions of multiple genetic and environmental factors that
dominant disorder that increases susceptibility to coro- contribute to hypercholesterolemia. Polygenic hyper-
nary heart disease (CHD). FH is caused by mutations Elevated plasma lipoprotein(a) (Lp[a]) is a disorder cholesterolemia is diagnosed by exclusion of other
in the gene encoding the LDL receptor, leading to characterized by increased concentrations of modified primary genetic causes, absence of tendon xanthomas,
two- to threefold increased plasma cholesterol concen- LDL particles in the plasma, in which the apo B100 and documentation that hypercholesterolemia is
trations in heterozygous individuals (prevalence of one protein of LDL is covalently bonded to Lp(a). Lp(a) has present in fewer than 10% of first-degree relatives.
in 500) and a three- to sixfold increase above the upper
limit of the reference range in homozygous individuals.
These patients may have characteristic physical findings
(see Plates 7-6 and 7-7). Familial defective apo B100 is a
disorder caused by mutations in the gene encoding apo
B100. Defective apo B100 apolipoprotein binding to the
LDL receptor results in a high plasma LDL concentra-
tion and an increased CHD risk.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 185

Plate 7-4 Endocrine System

Reverse cholesterol transport
Cholesterol from peripheral
tissues returned to liver

HIGH-DENSITY LIPOPROTEIN Direct mechanism. Indirect mechanism.
METABOLISM AND REVERSE Cholesterol-rich
CHOLESTEROL TRANSPORT Because of its apo E, form of apo B100
HDL1 is taken up by lipoproteins (LDL,
LDL receptors in the VLDL remnants)
taken up by liver
liver

High-density lipoproteins (HDLs) are small particles Nascent HDL synthesized TGRLP apo
that contain 50% lipid (phospholipid, cholesteryl esters, and secreted into circulation (apo B100 lipoproteins) B100
free cholesterol, triglyceride) and 50% protein. The by liver and gut
main apolipoproteins (apo) are apo AI (65%), apo AII
(25%), and smaller amounts of apo C and apo E. The LPL
two major subclasses of HDL are HDL2 and HDL3. apo C
HDL1 is a minor subclass and is associated with apo E. apo E
HDLs function to redistribute lipids among cells and
lipoproteins by a process referred to as reverse cholesterol apo A apo A, E CETP
transport, in which HDL acquires cholesterol from cells apo C II, III Cholesterol esters
and transports it either to other cells or to the liver. TGRLP Exchange of
apo E II, III cholesterol esters
The steps in the formation and metabolism of HDL Acquisition and apo C in HDL2a for
include the following: small nascent or precursor HDL apo A, C, E esterification of
disks composed of apo AI and phospholipid are synthe- Phospholipids free cholesterol Triglyc- triglycerides in
sized in the liver and small intestine; precursor HDL Cholesterol by nascent HDL
disks accept free cholesterol from cells or from other erides TGRLP mediated by
lipoproteins (triglyceride-rich lipoproteins [TGRL] mediated by CETP. HDL2b formed,
and chylomicron and very low-density lipoprotein LCAT. HDL3 and cholesterol-rich
[VLDL] remnants); and HDL free cholesterol is esteri- formed
fied by the apo AI–activated enzyme, lecithin–choles- form of apo B100
terol acyltransferase (LCAT). The esterified cholesterol HDL2a lipoprotein provided
increases its hydrophobicity, and it moves away from LCAT CETP for uptake by liver
the surface of the disk to form a cholesteryl ester–rich
core and changes the HDL shape from a disk to a apo A LCAT HDL cycle
sphere. The spherical, mature HDL2 particles function apo C
to remove excess cholesterol, and as they enlarge, the Nascent HDL apo E HDL3 Hepatic lipase HDL2b HDL2b hydrolyzed by
particle is termed HDL3. HDL acquires cholesterol by hepatic lipase to yield
aqueous transfer from cells (passive desorption) or by HDL cholesterol Free Free HDL3 and fatty acids
transport that is facilitated by cell surface–binding pro- mobilized from cholesterol fatty acids
teins. Several cell surface proteins facilitate the efflux of peripheral tissues
free cholesterol. For example, ABCA1 binds apo AI and
facilitates the transfer of free cholesterol and phospholi- Free Adipose
pids onto HDL. Mutations in the gene that encodes fatty acids tissue
ABCA1 can prevent this transfer process, resulting in a
lipid disorder called Tangier disease (see Plate 7-8). Free Trigly- Energy utilization
cholesterol cerides
Because of its apo E, HDL1 is taken up by LDL Fatty acids
receptors in the liver. In addition, cholesteryl ester Peripheral (extrahepatic) tissues
transfer protein (CETP) transfers cholesteryl esters (in
exchange for triglycerides) from HDL2 to TGRL (e.g., Muscle
VLDL, LDL, and remnants), which are then delivered
to the liver. An additional pathway of cholesterol redis- transport, HDL has other antiatherogenic properties. HDL formation because of lack of LCAT activation;
tribution from HDL is via scavenger receptor B1 For example, the HDL-associated enzyme paraoxonase resultant plasma concentrations are less than 10 mg/dL
(SR-B1) facilitation of selective uptake of cholesteryl serves to inhibit oxidation of LDL. In addition, HDL (reference ranges: low, less than 40 mg/dL; normal,
esters by the adrenal glands, gonads, and liver. The and apo AI stabilize the erythrocyte cell membrane and 40 to 60 mg/dL; desirable, greater than 60 mg/dL).
HDL2 particles that have been partially depleted of prevent transbilayer diffusion of anionic lipids, a step Increased plasma HDL concentrations are found
cholesteryl esters and enriched with triglycerides by that is required for prothrombin activation and throm- in individuals with CETP deficiency because of
CETP can be converted back to HDL3 by the action bus formation. the decreased transfer of cholesteryl esters from HDL
of hepatic lipase that hydrolyzes the triglycerides. to apo B-containing lipoproteins. CETP deficiency
Several alterations in the HDL pathway can result in homozygotes have HDL concentrations greater than
Reverse cholesterol transport—with a redistribution low or high plasma HDL concentrations. For example, 100 mg/dL.
of cholesterol from cells with excess (e.g., arterial mutations in the gene encoding apo AI can decrease
walls) to cells requiring cholesterol or to the liver for
excretion—is antiatherogenic. There is an inverse
relationship between plasma HDL concentration and
cardiovascular risk. In addition to reverse cholesterol

186 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-5 Lipids and Nutrition

300 Optimal Near optimal Borderline high High Very high
250 Ն190

Heart disease risk 200 160–189
LDL cholesterol (mg/dL)
150 130–159
100
Ͻ130
Ͻ100
HYPERCHOLESTEROLEMIA 50

Cholesterol has a chief role in the function of cell mem- 0
branes and serves as a precursor of steroid hormones. Multifactorial causes
However, when blood concentrations of low-density
lipoprotein (LDL) cholesterol exceed certain levels, Loss of Monogenic Monogenic Obesity
it is termed hypercholesterolemia. Hypercholesterolemia estrogen defect (increases
can predispose to atherosclerosis and increase the Diet high in cholesterol Multiple defect (familial (familial hepatic apo B
risk for vascular disease (e.g., coronary heart disease and saturated fat Aging regulator gene hypercho- defective secretion)
[CHD], cerebrovascular disease, and peripheral vascu- mutations lesterolemia) apo B100)
lar disease).
Intracellular Hepatic lipid
The National Heart Lung and Blood Institute of the cholesterol overload
National Institutes of Health has published a series of
three guidelines (1988, 1993, 2002), each updating the LDL receptor Production
existing recommendations for clinical management of synthesis of apo B100
high blood cholesterol. The Third Report of the Expert lipoproteins
Panel on Detection, Evaluation, and Treatment of Synthesis
High Blood Cholesterol in Adults is termed the Adult of defective Synthesis
Treatment Panel III (ATP III) and is the most recent LDL receptors of defective
version from the National Cholesterol Education apo B100
Program (NCEP). ATP III set cutoffs for blood LDL
cholesterol concentrations on the basis of cardiovascu- LDL uptake due LDL uptake due LDL uptake due to Overproduction of
lar risk. For example, a plasma LDL concentration less to lack of LDL to defective LDL defective apo B100 apo B100 lipoproteins
than 100 mg/dL is considered optimal. As plasma LDL receptors receptors increases LDL levels
levels increase, cardiovascular risk increases. The pres-
ence of risk factors (e.g., cigarette smoking, hyper- and the blood lipid profile are similar to those of famil- susceptibility to CHD. Other associations include mod-
tension, low plasma concentration of high-density ial hypercholesterolemia (see Plates 7-6 and 7-7). erate decrease in plasma HDL cholesterol concentra-
lipoprotein [HDL] cholesterol, family history of pre- tions, fasting hyperglycemia, obesity, and hyperuricemia.
mature CHD, age [men, ≥45 years; women, ≥55 years]) Familial hyperapobetalipoproteinemia (with over- Familial combined hyperlipidemia should be suspected
should modify the target for LDL cholesterol. For production of apo B100) and familial combined hyperli- in individuals with moderate hypercholesterolemia in
example, the presence of CHD or CHD risk equiva- pidemia are both inherited in an autosomal dominant combination with moderate hypertriglyceridemia in
lents (e.g., diabetes mellitus) decreases the LDL cho- fashion. Although the genetic defects underlying these the setting of a family history of premature CHD.
lesterol goal to less than 100 mg/dL; if there are two or conditions have yet to be identified (probably multiple Xanthomas are not seen in individuals with familial
more risk factors, the LDL cholesterol goal should be genetic defects), they are relatively common disorders hyperapobetalipoproteinemia or with familial com-
less than 130 mg/dL; if there is zero to one risk factor, and are associated with elevations of plasma LDL cho- bined hyperlipidemia.
the LDL cholesterol goal should be less than 160 mg/ lesterol and triglyceride concentrations and increased
dL. These targets may be modified when NCEP ATP
IV guidelines are published in the fall of 2011.

Many factors contribute to high plasma LDL con-
centrations. For example, diets high in saturated fats
and cholesterol lead to increased blood cholesterol con-
centrations. Although the level of cholesterol in the
blood is controlled at multiple sites, the primary regula-
tor is the LDL receptor pathway. LDL receptors are
present on the cell surface of most cells and mediate the
uptake of lipoproteins that contain the apolipoproteins
(apo) apo B100 and apo E (e.g., LDL, chylomicron rem-
nants, very low-density lipoproteins [VLDL], VLDL
remnants, and HDL1).

Familial hypercholesterolemia is a relatively common
disorder caused by mutations in the gene that encodes
the LDL receptor. Decreased synthesis or synthesis of
defective LDL receptors leads to increased plasma con-
centrations of LDL cholesterol (three- and sixfold
increased above the reference range in heterozygotes
and homozygotes, respectively) (see Plates 7-6 and 7-7).

Mutations in the gene that encodes apo B100 are rela-
tively common and lead to defective binding of LDL
cholesterol to the LDL receptor. The clinical findings

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 187