METABOLIC

SYSTEM DISORDER
PATHOLOGICAL FINDING
MS K23.1 & 2

dr.Joko S. Lukito, SpPA, dr. Soekimin, SpPA

Departemen Patologi Anatomi Fakultas Kedokteran
Universitas Sumatera Utara Medan
 DIABETES MELLITUS
Chronic disorder of carbohydrate, fat and protein metabolism
due to defective or deficient insulin secretory response.

• Demographics : 3% of world population,

54,000 deaths/year in US,
#7 leading cause of death.
Lifetime risk: type 1 – 0.5%, type 2 – 5%.

• Causes : destruction of islets due to pancreatitis, tumors, drugs

(steroids, thiazides, pentamidine), hemochromatosis (“bronze
diabetes” due to hemosiderin deposition in pancreas), hereditary
ceruloplasmin deficiency, surgery, infections (congenital rubella,
CMV, coxsackievirus , endocrinopathies (pituitary, adrenal,
pregnancy), gestational diabetes or idiopathic.
 DIAGNOSIS
• Blood glucose rises markedly for a sustained

period.

• High fasting glucose.

• Impaired glucose tolerance.

 Long term complications
• Damage to blood vessels in kidneys (nodular
Kimmelstiel-Wilson glomerulopathy,
pyelonephritis, papillary necrosis)
• Eyes (exudative and proliferative retinopathy)
• Nerves (symmetric polyneuropathy);
Brain (stroke)
• Peripheral vascular disease and coronary artery
heart disease
• Morbidity / death
 Insulin-Dependent Diabetes Mellitus (IDDM)
• Juvenile onset, Type 1 10% of all cases
• Beta cell mass causing severe, absolute lack of
insulin.
• Onset : age < 20 years, normal weight, decreased blood
insulin, anti-islet cell antibodies (+), DKA common.
• Islet cell destruction :
due to genetic predisposition, autoimmunity, environmental
insult; initially with mononuclear cell infiltrates
• Autoimmunity :
usually chronic (years); clinical disease when 90% of islet
cells are destroyed.
Associated with CD8+ T cell infiltrate, Coxsakie vir.
 Insulin-Dependent Diabetes Mellitus (IDDM)
• Clinical : PPP (polyuria, polydipsia, polyphagia)
and DKA
• Low/absent plasma insulin, high plasma
glucagon, unstable glucose tolerance (very
sensitive to changes in insulin, diet, exercise,
infection, stress),
• Presence of free fatty acids (due to breakdown of
adipose stores), which produces ketone bodies
(acetoacetic acid and beta-hydroxybutyric acid)

• Micro: early insulinitis with marked islet atrophy

and fibrosis and severe beta cell depletion
 Non-Insulin Dependent Diabetes Mellitus
• Adult onset, NIDDM; type 2 80-90% of cases of
diabetes
• Usually > 30 years old, obese (80% of cases).
• Relative insulin deficiency is due to insulin resistance or
derangement in beta cell secretion of insulin
• Mild/moderate insulin deficiency; beta cells may be
“exhausted” due to chronic hyperglycemia and persistent
beta cell stimulation.
• Insulin resistance in peripheral tissues also seen in obesity
and pregnancy.
The central role of fat
cells in regulating
insulin resistance.
Adipocytes produce
factors that increase
or decrease insulin
resistance. Certain
antidiabetic drugs
modify insulin
resistance by
affecting the
synthesis of
adipocyte-derived
factors via the
peroxisome
proliferator-activated
receptor γ (PPAR-γ)
nuclear receptor. TNF,
tumor necrosis factor.
 Histology :
1. Alveoli
2. Islets of Langerhans :
a cells
b cells
d cells
3. Interlobular septa
4. Interlobular ducts

Normal pankreas with islet of Langerhans. Endocrine function :

1. Insulin
(beta cells)
2. Glucagon
(alpha cells)
3. Somatostatin
(delta cells)
 Microscopic findings:
• Type 1 :
inconsistent reduction in number and size of islets,
uneven insulinitis (T lymphocytes).
• Type 2 :
• subtle reduction in islet cell mass, amyloid
replacement of islets due to amylin fibrils (also
seen in aging nondiabetics);
• associated with marked fatty replacement.
• Infants of diabetic mothers – islet cell
hypertrophy/hyperplasia.
The pancreas is a compound, acinar, serous , exocrine gland with
islets of endocrine cells. This low-magnification view shows the
organization of acinar parenchyma into irregular lobules,
separated by prominent clear spaces. The amount of space is an
artefact. Since the size of interlobular spaces (which contain
loose connective tissue) is easily altered by manipulation
(stretching or compression). Connective tissue of an interlobular
septum is visible at right, including a prominent blood vessel.
This is an insulitis of an
islet of Langerhans
(type I DM). The
presence of the
lymphocytic infiltrates in
this edematous islet
suggests an
autoimmune
mechanism for this
process. The
destruction of the islets
leads to an absolute
lack of insulin that
characterizes type I
DM.
An islet of Langerhans demonstrates amorphous pink deposition of
amyloid in a patient with type II diabetes mellitus.
 Complications of diabetes

1. Microangiopathy

2. Nephropathy

3. Retinopathy

4. Neuropathy

5. Dermopathy
 Microangiopathy
Microangiopathy: diffuse basement membrane thickening
with protein leakage in capillaries.
Red Skin and Rubeosis Facei
Facial involvement rubeosis facei d/t
dilatation of superficial venous plexus.
In the eye grounds and skin.
Periungual telangiectasia.
Assumed to play a role in diabetic neuropathy
diabetic foot.
Increased tendency for diabetic platelets to aggregate 
plasma viscosity and sluggish microcirculation.
Gangrene foot

Diabetic dermopathy

Diabetic Bullae,Fingers
 Dermatologic manifestation

• Skin in diabetic patients is generally thicker than that

of non-diabetics collagen

• Advanced glycosylation end products yellowing

of skin and nails.
CUTANEOUS INFECTIONS IN DIABETES MELLITUS

• Etio : Candida, Pseudomonas, Dermatophytosis

• Foot ulcer.

• Foliculitis  carbuncle

Candidiasis, Fingernails
Gangrenous necrosis and
ulceration involving the lower
extremity is shown here.
Diabetics have accelerated
atherosclerosis that can be
extensive to involve
peripheral vasculature and
predispose to this
complication.
A diabetic foot with a
previous healed
transmetatarsal
amputation demonstrates
an ulcer in the region of
the ankle.
 Vascular complications
• Atherosclerosis in aorta and large/medium sized
vessels
• Myocardial infarction : common cause of death, M=F
• Gangrene of lower extremities; relative risk is 100:1
• Micro :
hyaline arteriolosclerosis, associated with
hypertension, more common/severe in diabetes but
not specific; amorphous hyaline thickening in arteriolar
wall
Hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent
arteriole in the kidney. The amorphous nature of the thickened vascular
wall is evident. (Periodic acid-Schiff.) (Courtesy of Dr. M. A. Venkatachalam,
Department of Pathology, University of Texas Health Science Center at San Antonio, San
Antonio, TX.)
 Nephropathy

• #2 cause of death in patients with diabetes after MI.

• Glomeruli - capillary basement membrane thickening.

• Nodular glomerulosclerosis :
ball-like deposits of laminated matrix within mesangial core
of lobule;
push capillary loops to periphery, may have perinodular
halos; called Kimmelstiel-Wilson lesion and
may contain trapped mesangial cells;
low sensitivity (10-35%) but highly specific for diabetes
mellitus.
 Nephropathy Cont’d

• Diffuse glomerulosclerosis: diffuse increase in mesangial

matrix, mesangial cell proliferation, basement membrane

thickening; seen in most patients with diabetes mellitus after 10

years; when marked, causes nephrotic syndrome; not specific

• Also renal atherosclerosis and arteriolosclerosis; changes to

efferent arteriole are specific for diabetes

• Pyelonephritis and necrotizing papillitis also common.

A
A renal glomerulus demonstrate
nodular glomerulosclerosis with
diabetes mellitus. This lesion is
quite characteristic for diabetes
mellitus. A diffuse
glomerulosclerosis may also be
seen.

Ascending UTI. Diabetics prone to

develop infections in general. Pic :
budding cells, pseudohyphae Candida
albicans (PAS stain) in renal pelvis.
A renal glomerulus with
nodular glomerulosclerosis,
along with hyaline
arteriolosclerosis in the small
arteriole to the lower right of
the glomerulus, is shown here
with PAS stain.
 Ocular Manifestations
• # 4 cause of blindness in US

• Associated with retinopathy, cataracts, glaucoma,

infection.

normal retinae
Cataracts of the crystalline lens with
opacification.

Diabetic retinopathy on funduscopic

examination.
 DIABETIC NEUROPATHY
Autonomic Neuropathy
the first nervous tissue affected in diabetics 
nonmyelinated nerve fibers, such as those of the
autonomic nervous system
Diabetics often develop sensory neuropathy on the feet,
especially with long-standing disease. The clinical
presentation usually involves tingling and numbness
starting in the toes. The level of neuropathy may vary
from mild numbness of the distal toes to profound
anesthesia and neuropathic ulcers. Thermal sensitivity
 Lipid
Metabolic
Disorder
 Hyperlipidemia
• Disorders caused by the accumulation of lipids are
called lipidoses.
• Other enzyme abnormalities result in the body being
unable to properly convert fats into energy are called
fatty acid oxidation disorders.

Hyperlipidemia : strong
risk factor for ischemic
heart disease.
Obese (abdominal
obesity more dangerous
than subcutaneous
obesity).
• Hyperlipidemia is often secondary to uncontrollable
diabetes, biliary cirrhosis, and lipoid nephrosis.
• Excess proliferation of fat cells  lipoma.
• In genetic lipid storage diseases, lipid accumulates
because of a disturbance in lipid metabolism. Genetic
diseases due to gene defects result in abnormal lipid
metabolism.
• Large accumulation of lipid appears in many cells, but
particularly the reticuloendothelial cells of the lymph
nodes, liver, spleen, and bone marrow.
• Abnormal lipid storage occurs in Niemann-Pick,
Gaucher's, and Tay-Sachs diseases.
Hepatic fatty change

The lipid accumulates in the hepatocytes as vacuoles. These vacuoles have a

clear appearance with H&E staining. The most common cause of fatty change
in developed nations is alcoholism. In developing nations, kwashiorkor in
children is another cause. Diabetes mellitus, obesity, and severe gastrointestinal
malabsorption are additional causes.
 GAUCHER'S DISEASE
• Glucocerebrosides, which are a product of fat
metabolism, accumulate in tissues.
• The most common lipidosis.
• Leads to an enlarged liver and spleen and a brownish
pigmentation of the skin. Accumulations of
glucocerebrosides in the eyes cause yellow spots
called pingueculae to appear.
• Accumulations in the bone marrow can cause pain
and destroy bone.
• Adults form, infantile form and juvenile form.
• Th/ : enzyme replacement therapy (intravenous),
every 2 weeks.
 TAY-SACHS DISEASE

• Gangliosides  products of fat metabolism,

accumulate in tissues.
• At a very early age, children with this disease become
progressively retarded and appear to have floppy
muscle tone.
• Spasticity followed by paralysis, dementia, and
blindness.
• These children usually die by age 3 or 4.
• Tay-Sachs disease can be identified in the fetus by
chorionic villus sampling or amniocentesis.
• The disease cannot be treated or cured.
 NIEMANN-PICK DISEASE
• Deficiency of a specific enzyme results in the accumulation of
sphingomyelin or cholesterol.
• Several forms : depending on the severity of the enzyme
deficiency and thus accumulation of sphingomyelin or
cholesterol.
• Type A : Children fail to grow properly and have multiple
neurologic problems  die by age 3.
• Type B : develop fatty growths in the skin, areas of dark
pigmentation, and an enlarged liver, spleen, and lymph nodes;
may be mentally retarded.
• Type C : develop symptoms in childhood, with seizures and
neurologic deterioration.
• None of the types of Niemann-Pick disease can be cured, and
children tend to die of infection or progressive dysfunction of
the central nervous system.
 Xanthelasma

• Xanthelasma  most common form of xanthoma,

characterized by one or more yellowish plaques on
the eyelid or in the periorbital skin.

• Microscopic :

small aggregates of large, pale staining foam cells

in the upper dermis.

Inflammatory cells (-).

There is no fibrosis.
Xanthelasma
palpebra
Xanthelasma of the chest

Eruptive xanthoma (elbow)

 PROTEIN
CALORIE
MALNUTRITION
 Malnutrition
• Malnutrition may be due to inadequate food
absorption or inadequate food intake (inadequate
supply, increased requirements).
• The diagnosis of malnutrition depends on an accurate
dietary history, evaluation of height, weight, head
circumference and past rates of growth, measurement
of midarm circumference and skinfold thickness and
other tests.
• Chronic malnutrition : deficits of more than a single
nutrient. There is usually associated immunologic
insufficiency (white blood cell count < 1500/mm3 and
anergy to skin test antigens).
 Malnutrition
• Insufficient protein intake;
impaired absorption
(chronic diarrhea),
abnormal losses
(nephrosis, burns) or
impaired synthesis (chronic
liver disease).
• Underdeveloped countries,
affecting children from
infancy to about 5 years of
age.
 Marasmus (Infantile Atrophy, Athrepsia)
• In most cases, marasmus is due to inadequate caloric
intake, but may also be due to metabolic abnormalities
or congenital malformations.
• Clinical :
– failure to gain weight followed by weight loss and
finally emaciation.
– Fat is loss last from the cheeks.
– The abdomen may be flat or distended.
– There is muscle atrophy and hypotonia.
– The basal metabolic rate is reduced.
– The infant may be constipated or have the
"starvation type" of diarrhea with mucus.
Percentage of population affected by malnutrition by country,
according to United Nations statistics.
 Kwashiorkor
Symptoms :
– lethargy,
– apathy,
– irritability to inadequate growth,
– loss of muscular mass,
– secondary immunodeficiency and
– edema.
– renal function is decreased,
– the liver and the heart may enlarge.
– dermatitis is common;
– the hair is sparse, thin and dyspigmentated.
– Infections,
– vomiting and diarrhea are common.
– vitamin and mineral deficiencies;
– delayed bone growth.
– Mental changes may occur, followed by stupor, coma and
death.
 Kwashiorkor
Laboratory data:
• low albumin concentration
• low plasma glucose
• ketonuria
• low plasma amino acids
• decresed K+, Mg++
• low cholesterol

The treatment is based on management of the associated

conditions (infections, dehydration, anemia, diarrhea) and
institution of adequate diet.
Mental and physical retardation may be permanent.
Protein Calorie Malnutrition Immune Function in Humans
Humoral Immunity Response
1. Serum immunoglobulin levels Raised or Normal
2. Secretory IgA Decreased
3. Circulating B cells Decreased or N
4. Plaque forming cells Decreased

Cellular Immunity Response

1. PHA Decreased Decreased
2. Immunity to intracellular organisms Decreased
3. Circulating T Cells Decreased
4. Lymphokine production Decreased
 GOUT / TOPHI
• Gout  arthritis / inflammation in some joints because of uric
acid accumulation.
• Predilections : joints of extremities
– large toe, knee, ankle, foot  >>>
– arms (hand, wrist, and elbow)  less.
– fingers (uncommon).

• Symptoms :
– Sudden, intense joint pain, which often first occurs in the early morning
hours.
– Swollen joint
– Warm
– Red or purple skin around the joint.
 Uric Acid

• Uric acid : red meats , internal organs (liver,

kidneys, tongue, heart), some shellfish,

anchovies (teri), peanut.

• Normal levels for men = < 7mg/dl and slightly

less for most women.

 GOUT
• Abnormal deposits of sodium urate crystals in the joint
cartilage and later release into the joint fluid.
• Uric acid crystals can also form in the kidney  kidney
stones.
• Sodium urate is formed from uric acid, a natural
chemical in the body. Uric acid comes from the natural
breakdown of proteins.
• Uric acid in normal amounts remains dissolved in the
blood, easily passes through the kidneys, and leaves
the body as waste. Uric acid in high amounts,
however, makes a person more likely to develop gout.