MS1 K32 dan MS2 K6

Departemen Patologi Anatomi

Fakultas Kedokteran
Universitas Sumatera Utara Medan
2016
MS1-K32

LIPID METABOLIC
DISORDER
 HYPERLIPIDEMIA

LIPIDOSES • Accumulation of lipids

Fatty acid
• The body being unable to
oxidation
disorders properly convert fats into energy

LIPOMA • ↑proliferation of fat cells

Hyperlipidemia …

HYPERLIPIDEMIA
• Strong risk factor for ischemic heart disease

OBESE
• Abdominal obesity more dangerous than
subcutaneous obesity
Hyperlipidemia often secondary to:
• Uncontrollable diabetes
• Biliary cirrhosis, and
• Lipoid nephrosis
Hyperlipidemia …
 HYPERCHOLESTEROLEMIA
FAMILIAL
• Autosomal dominan
 Paling sering, 1 : 500 (US)
 Heterozygote
(homozygote sekitar 1 dalam 1 juta orang)
• LDL serum ↑
• Mutasi gen penyandi reseptor permukaan sel yang
membersihkan LDL serum Cholesterol mengendap
pada:
– Arteri
– Tendon
– Kulit
 HEPATIC FATTY CHANGE
• The most common cause in developed
nations is:
– ALCOHOLISM
– KWASHIORKOR (in children)
• Additional causes:
– DIABETES MELLITUS
– Obesity, and
– Severe gastrointestinal malabsorption
 The LIPID ACCUMULATES in the hepatocytes as
vacuoles (Vacuoles have a clear appearance with H&E staining)

Hepatic fatty change

 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 in many cells, particularly:
– Reticulo-endothelial cells of the lymph nodes
– Liver, Spleen, and
– Bone marrow
Genetic lipid storage diseases …

Abnormal lipid
storage occurs in:
• Niemann-Pick
• Gaucher's
• Tay-Sachs diseases
 NIEMANN-PICK DISEASE
• Deficiency of a specific enzyme results in the
accumulation of sphingomyelin / cholesterol
• Depending on the severity of the enzyme deficiency &
accumulation of sphingomyelin/cholesterol  several
forms. Types:
A. Children fail to grow properly & have multiple neurologic
problems  die by age 3
B. Develop fatty growths in the skin, areas of dark pigmentation, &
an enlarged liver, spleen, and lymph nodes; may be mentally
retarded
C. Develop symptoms in childhood, with seizures, & neurologic
deterioration
• Can not cured
• Children tend to die of infection / progressive dysfunction
of the CNS
Niemann-Pick disease in liver

The hepatocytes & Kupffer cells have a foamy,

vacuolated appearance due to deposition of lipids.
 GAUCHER'S DISEASE
• GLUCOCEREBROSIDES
– Product of fat metabolism, accumulate in tissues
• The most common lipidosis
• Leads to:
– Enlarged liver & spleen
– Brownish pigmentation of the skin
• Accumulations of glucocerebrosides in :
– Eyes cause yellow spots called PINGUECULAE
– Bone marrow can cause PAIN and DESTROY BONE
• Types:
– Adults form, infantile form, and juvenile form
• Therapy:
– Enzyme replacement therapy (intravenous), every 2 weeks.
 TAY-SACHS DISEASE
• GANGLIOSIDES
– Products of fat metabolism, accumulate in tissues
(CNS neural)
• Autosomal recessive
– 1/2 dari keturunan heterozigot & ‘silent carrier’
(pembawa mutasi gen asimptomatik)
• At a very early age
– Children become progressively RETARDED
– Appear to have FLOPPY MUSCLE TONE
• Spasticity followed by paralysis, dementia, and blindness
(Cherry-red in macula)
 Children usually die by age 3 or 4
Tay-Sachs disease …

• Can be identified in the fetus by:

– Chorionic villus sampling
– Amniocentesis
• Cannot be treated or cured.
• Histologic:
– Neurons are ballooned with cytoplasmic vacuoles
– Markedly distended lysosome filled with gangliosides
• Stains for fats:
– Oil red O
– Sudan black B
 Ganglion cells in
Tay-Sachs disease

Neurons ballooned with

cytoplasmic vacuoles
(lysosome filled with
gangliosides)
 XANTHELASMA
• Most common form of xanthoma
• Characterized by:
– One or more yellowish plaques on:
• The eyelid or
• In the periorbital skin
Xanthelasma
palpebra
Xanthelasma of the chest

Eruptive xanthoma (elbow)

Xanthelasma …

Microscopic
• Small aggregates of
large, pale staining foam
cells in the upper dermis
(Lipid-Laden histiocytes)
• Inflammatory cells (-)
• No fibrosis.
 PROTEIN
CALORIE
MALNUTRITION
 MALNUTRITION
• Due to:
– Inadequate food absorption
– Inadequate food intake (inadequate supply, ↑
requirements)
• Diagnosis depends on:
– Dietary history
– Evaluation of height, weight, head
circumference & past rates of growth
– Measurement of mid-arm circumference &
skinfold thickness
– Other tests
Malnutrition …

• Chronic malnutrition:
– Deficits of > a single nutrient
– Usually associated immunologic insufficiency
• White blood cell count < 1500/mm3
• Anergy to skin test antigens
Malnutrition …

• Insufficient protein intake

– Impaired absorption (chronic diarrhea)
– Abnormal losses (nephrosis, burns)
– Impaired synthesis (chronic liver disease)
• Underdeveloped countries
– Affecting: infancy - 5 yrs old
 Marasmus
(Infantile Atrophy, Athrepsia)
• Due to:
– Inadequate caloric intake
– Metabolic abnormalities
– Congenital malformations
• Clinical :
– Failure to gain weight followed by weight loss &
emaciation
– Fat loss (cheeks)
– Abdomen flat / distended
– Muscle atrophy & hypotonia.
– Basal metabolic rate (BMR) ↓
– Infant constipated / "starvation type" of diarrhea with
mucus
Percentage of population affected by malnutrition by
country, according to United Nations statistics.
 Kwashiorkor
Symptoms :
• Lethargy • Dermatitis (common)
• Apathy • Hair (sparse, thin,
• Irritability to inadequate dyspigmentated)
growth • Infections
• Loss of muscular mass • Vomiting & diarrhea
• Secondary (common)
immunodeficiency • Vitamin & mineral
• Edema deficiencies
• Renal function ↓ • Delayed bone growth
• Liver & Heart  may • Mental changes 
enlarge followed by stupor, coma
and death
Kwashiorkor …

• Laboratory data:
– Albumin concentration ↓
– Plasma glucose ↓
– Ketonuria
– Plasma amino acids ↓
– K+ & Mg++ ↓
– Cholesterol ↓
• The treatment is based on :
– Management of the associated conditions (infections,
dehydration, anemia, diarrhea)
– Institution of adequate diet
• Mental & physical retardation  may be permanent
MS2-K6

DIABETES MELLITUS
 DIABETES MELLITUS
Chronic disorder of carbohydrate, fat and protein
metabolism due to
defective / deficient insulin secretory response

Lifetime risk:

• Type 1 – 0,5%
• Type 2 – 5 %
Diabetes mellitus …

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, coxsackie virus)
• Endocrinopathies (pituitary, adrenal, pregnancy)
• Gestational diabetes
• Idiopathic
 DIAGNOSIS

• Blood glucose ↑
 Markedly for a sustained period

• Fasting glucose ↑

• Impaired glucose tolerance

Insulin-Dependent Diabetes Mellitus
(IDDM)
• Juvenile onset
• Type 1 (10% of all cases)
• β-cell mass ↓
 causing severe / absolute lack of insulin
• Clinics:
– Onset age < 20 years
– Normal weight
– ↓ blood insulin
– Anti-islet cell antibodies (+)
Insulin-Dependent Diabetes Mellitus (IDDM) …

• Islet cell destruction:

– Due to:
• Genetic predisposition,
• Autoimmunity
• Environmental insul
– Initially:
• Mononuclear cell infiltrates
• Autoimmunity:
– Usually chronic (years)
– 90% islet cells destroyed  clinical disease
– Associated with CD8+ T cell infiltrate, Coxsakie virus
Insulin-Dependent Diabetes Mellitus (IDDM) …

• Microscopic:
– Early insulinitis with marked islet atrophy and
fibrosis and severe β-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
 due to insulin resistance / derangement in β-cell secretion
of insulin
• Mild/moderate insulin deficiency
– β-cells “exhausted” due to chronic hyperglycemia &
persistent β-cell stimulation
• Insulin resistance in peripheral tissues
– Also seen in obesity & pregnancy
THE CENTRAL ROLE OF FAT CELLS IN
REGULATING INSULIN RESISTANCE
 HORMONE PRODUCTION IN PANCREATIC
ISLET CELLS
Insulin in β cells (A), glucagon in α cells (B), and somatostatin in δ cells (C)
 Microscopic findings:
• Type 1 :
– Inconsistent ↓ number & size of islets
– Uneven insulinitis (T-lymphocytes)
• Type 2 :
– ↓ islet cell mass
– Amyloid replacement of islets
 due to amylin fibrils (also seen in aging
nondiabetics)
– Marked fatty replacement
• Infants of diabetic mothers
– Islet cell hypertrophy/hyperplasia
 Insulitis of an islet of
Langerhans
(type I DM)
Autoimmune mechanism
 lymphocytic infiltrates in
edematous islet
The destruction of the islets
leads to an absolute lack of
insulin (characterizes type I DM)
An islet of Langerhans demonstrates amorphous pink deposition of
amyloid in a patient with type II diabetes mellitus.
 Long term complications

Damage to:

Blood vessels in kidneys Brain

• Nodular Kimmelstiel-Wilson • Stroke
glomerulopathy, pyelonephritis,
papillary necrosis Peripheral vascular disease
Eyes
Coronary artery heart disease
• Exudative and proliferative
retinopathy Morbidity / death
Nerves
• Symmetric polyneuropathy
 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 ↑ & sluggish microcirculation
Gangrene foot

Diabetic dermopathy

Diabetic bullae fingers

 Dermatologic manifestation
• Skin in diabetic patients
– Generally thicker than that of non-diabetics  collagen
• Advanced glycosylation end products  yellowing of skin and nails
 CUTANEOUS INFECTIONS IN
DIABETES MELLITUS
Candidiasis, Fingernails

• Etiology:
– Candida, Pseudomonas, Dermatophytosis
• Foot ulcer
• Foliculitis  carbuncle
Gangrenous necrosis and
ulceration involving the lower A diabetic foot with a previous
extremity is shown here. Diabetics healed transmetatarsal amputation
have accelerated atherosclerosis demonstrates an ulcer in the
that can be extensive to involve region of the ankle.
peripheral vasculature and
predispose to this complication.
 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
• Microscopic:
– Hyaline arteriolosclerosis, associated with
hypertension, more common/severe in diabetes but
not specific
– Amorphous hyaline thickening in arteriolar wall
HYALINE ARTERIOLOSCLEROSIS
 Nephropathy
• 2nd 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 (Kimmelstiel-Wilson lesion)
May contain trapped mesangial cells
Low sensitivity (10-35%), but highly specific for
diabetes mellitus
 Cont’d

Nephropathy
• 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 & 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
PROTEIN CALORIE
MALNUTRITION
 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 & later release into the joint fluid
• Uric acid crystals 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, makes a person more likely to
develop gout
15-25
grams
 HYPER-THYROIDISM
• aka, thyrotoxicosis
• Diffuse
• Nodular
• Adenoma
• Carcinoma
• Neonatal
• Secondary to TSH pituitary adenoma
 HYPER-THYROIDISM
• HYPERMETABOLISM
• Tachycardia, palpitations
• Increased T3, T4
• Goiter
• Exophthalmos
• Tremor
• GI hypermotility
• Thyroid “storm”, life threatening
 HYPO-THYROIDISM
• 1° Developmental
• 1° Surgery, I-131, external radiation
• 1° Auto-immune (i.e., Hashimoto’s)
• 1° Iodine deficiency
• 1° Li+, iodides, p-aminosalicylates
• 2° (pituitary)
• 3° (hypothalamic, rare)
 HYPO-THYROIDISM
• Cretinism
– Severe retardation
– CNS/Musc-skel
– Short stature
– Protruding tongue
– Umbilical hernia
– Maternal iodine defic.
• Myxedema (coma)
– Sluggishness
– Cool skin
 THYROIDITIS
• Hashimoto (Auto-Immune) (Lymphoid
follicles with germinal centers), MOST
COMMON cause of acquired hypothyroidism
in USA

• Subacute Granulomatous (DeQuervain)

• Subacute Lymphocytic (just like

Hashimoto’s but NO fibrosis and no
germinal centers), often post-partum
 GRAVES DISEASE
(aka, diffuse toxic goiter)
• HYPERTHYROIDISM
• EXOPHTHALMOS
• PRE-TIBIAL MYXEDEMA
• Autoimmune, auto-antibodies to TSH
SCALLOPING
GRAVES DISEASE
(aka, diffuse toxic goiter)

PLUMMER DISEASE
(aka, nodular toxic goiter)
HARDER TO TREAT
Surg
PTU (Propyl Thio Uracil)
I-131
 GOITERS
(aka, thyromegaly, diffuse or nodular)
• IODINE deficiency
• Increased TSH
• Goitrogens, e.g., cabbage, Brussels
sprouts, cauliflower, turnips, cassava)
• Associated with HYPO thyroidism
eventually, NOT hyperthyroidism
G
O
I
T
E
R
Thyroid Neoplasms
• “Nodules” vs. true neoplasms

• Adenomas vs. Carcinomas

 “NODULES”
• Solitary vs. Multiple
• Younger vs. Older
• Male vs. Female
• Hx. neck radiation vs. NO Rx.
• “Cold” vs. HOT (really NOT-
cold)
NEOPLASMS
• ADENOMAS • CARCINOMAS
–FOLLICULAR –FOLLICULAR
–HÜRTHLE
(oxyphilic) –PAPILLARY
– MEDULLARY
(AMYLOID)
– ANAPLASTIC
(worst)
HÜRTHLE CELL ADENOMA, note “atypia”
ORPHAN ANNIE CELLS in PAPILLARY CARCINOMA
MEDULLARY CARCINOMA of the thyroid with “HYALINIZATION”, i.e.,

AMYLOID!!!
 HYALINIZATION showing APPLE GREEN
birefringence in CONGO RED stain, i.e., AMYLOID
BIOLOGIC BEHAVIOR
• Papillary CA
 lymph nodes

• Follicular CA
 blood vessels, bone
35-50 mg
 PTH
• HYPOCALCEMIA is MAIN
STIMULUS (9-10.5 mg/dl)

• ANTAGONIZES CALCITONIN
PARATHYROID DISORDERS
• HYPER-
– PRIMARY (usually adenomas)
– SECONDARY (LOW CA++ of Renal Failure)
• HYPO-:
– Surgical
– Congenital
– Familial
– Idiopathic
• PSEUDO-HYPO-
– (end organ resistance)
HYPER-PARATHYROIDISM
• Bone pain, fractures
• Nephrolithiasis
• Constipation, ulcers, gallstones
• Depression, lethargy
• Weakness, fatigue
• Calcifications, esp. VALVES
HYPO-PARATHYROIDISM
• Neuromuscular irritability
• Mental status change
• Parkinsonism like effects
• Lens calcification* (paradox)
• Widened QT interval
• Defective, carious, teeth
THANK YOU