Acanthosis Nigricans

- Terjadi karena sesuatu yg trigger epidermal keratinocyte dan dermal fibroblast proliferation
- Factornya bisa
o Benign : Insulin yang tinggi, atau insulinlike growth factor (IGF) atau Tyrosine Kinase Receptors
(epidermal growth factor receptor / EGFR dan fibroblast growth factor receptor / FGFR)
o Malignant : biasanya TGF-alpha (transforming growth factor-alpha) karena mirip EGFR
- Causes:
o Insulin resistance. Most people who have acanthosis nigricans have also become resistant to insulin.
Insulin is a hormone secreted by the pancreas that allows your body to process sugar. Insulin
resistance is what eventually causes type 2 diabetes.
o Hormonal disorders. Acanthosis nigricans often occurs in people who have disorders such as ovarian
cysts, underactive thyroids or problems with the adrenal glands.
o Certain drugs and supplements. High-dose niacin, birth control pills, prednisone and other
corticosteroids may cause acanthosis nigricans.
o Cancer. Acanthosis nigricans also sometimes occurs with lymphoma or when a cancerous tumor
begins growing in an internal organ, such as the stomach, colon or liver.

Obesity
- Overweight :
o Grade 1 overweight (overweight) = BMI 25 -29
o Grade 2 overweight (obese) = BMI 30 – 39
o Grade 3 overweight (severe or morbid obesity) = BMI >40
- Some authorities advocate a definition of obesity based on percentage of body fat, as follows:
o Men: Percentage of body fat greater than 25%, with 21-25% being borderline
o Women: Percentage of body fat great than 33%, with 31-33% being borderline
- Comorbidities :
o Respiratory: Obstructive sleep apnea, [4] greater predisposition to respiratory infections, increased
incidence of bronchial asthma, and Pickwickian syndrome (obesity hypoventilation syndrome [176] )
o Malignant: Reported association with endometrial (premenopausal), prostate, colon (in men), rectal
(in men), breast (postmenopausal), gall bladder, gastric cardial, biliary tract system, pancreatic,
ovarian, renal, and possibly lung cancer, as well as with esophageal adenocarcinoma and multiple
myeloma [5, 6, 7]
o Psychological: Social stigmatization and depression
o Cardiovascular: Coronary artery disease, [8] essential hypertension, left ventricular hypertrophy, cor
pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, and pulmonary
hypertension of obesity
o Central nervous system (CNS): Stroke, idiopathic intracranial hypertension, and meralgia
paresthetica
o Obstetric and perinatal: Pregnancy-related hypertension, fetal macrosomia, and pelvic dystocia [9]
o Surgical: Increased surgical risk and postoperative complications, including wound infection,
postoperative pneumonia, deep venous thrombosis, and pulmonary embolism
o Pelvic: Stress incontinence
o Gastrointestinal (GI): Gall bladder disease (cholecystitis, cholelithiasis), nonalcoholic steatohepatitis
(NASH), fatty liver infiltration, and reflux esophagitis
o Orthopedic: Osteoarthritis, coxa vera, slipped capital femoral epiphyses, Blount disease and Legg-
Calvé-Perthes disease, and chronic lumbago
o Metabolic: Type 2 diabetes mellitus, prediabetes, metabolic syndrome, and dyslipidemia
o Reproductive (in women): Anovulation, early puberty, infertility, hyperandrogenism, and polycystic
ovaries
o Reproductive (in men): Hypogonadotropic hypogonadism
 o Cutaneous: Intertrigo (bacterial and/or fungal), acanthosis nigricans, hirsutism, and increased risk for
cellulitis and carbuncles
o Extremity: Venous varicosities, lower extremity venous and/or lymphatic edema
o Miscellaneous: Reduced mobility and difficulty maintaining personal hygiene
- Duerenberg equation  utk hitung body fat index
o body fat percentage = 1.2(BMI) + 0.23(age) - 10.8(sex) - 5.4
o Sex =
 Male = 1, female = 0
o Men: Percentage of body fat greater than 25%, with 21-25% being borderline
o Women: Percentage of body fat great than 33%, with 31-33% being borderline
- Obesity gene :
- Pathogenesis of common obesity:
o Obesity can result from increased energy intake, decrease energy expenditure, or combination
o Di tubuh, terdapat “set point” yang mengatuh body weight, yang diatur oleh sensing system yang
berada di sekitar adipose tissue dan receptor “adipostat” di hypothalamus
o Saat fat stores depleted, adipostat signal run low  hypothalamus respond dengan stimulasi hunger
and decrease energy expenditure
- Leptin in typical obesity
o Bisa terjadi “leptin resistance” yang mempengaruhi seseorang jadi obese
o Tapi masih blm jelas mekanismenya
- Pathologic consequences
o Insulin resistance and type 2 DM
 Hyperinsulinemia and insulin resistance sering berpengaruh pada obese
 Bisa berpengaruh pada fat, muscle, dan liver
 Major factors:
 Insulin  inducing receptor down regulation
 Free fatty acid yang terproduksi dan bisa impaired insuliv action
 Intracellular lipid accumulation
 Several circulating peptides produced by adipocytes (TNF-alpha, IL-6, RBP4,
adipokine)
o Reproductive disorders
 Male hypogonadism :
 Reduced plasma testosterone
 Reduced sex hormone binding globulin (SHBG)
 Increased estrogen (adrenal adrogen diubah jadi estrogen di adipose tissue)
 Bisa gynecomastia
 Female :
 Menstrual abnormalities (biasanya di upper body obesity)
 Increased androgen production
 Decreased SHBG
 Increased peripheral conversion from androgen to estrogen
o Cardiovascular diseases
 Obesity especially abdominal obesity berhubungan dengan atherogenic lipid profile:
 Increase LDL
 Increase VLDL
 Increase Trigliceride
 Decrease HDL
 Decrease level of vascular protective adipokine adiponectin
o Pulmonary disease
 Reduced chest wall compliance
 Increase work of breathing
 Increased RR due to metabolic rate
 Decreased functional residual capacity and expiratory reserve volume
 SLEEP APNEA (gabisa nafas pas tidur, sampe kebangun)
o Hepatobilliary system
 Nonalcoholic Fatty Liver Disease (NAFLD)  Nonalcoholic Steato Hepatitis (NASH) 
cirrhosis / hepatocellular carcinoma
 Increase biliary secretion of cholesterol, supersaturation of bile, higher incidence of
gallstones
o Bone, joint, cutaneous disease
  OA
 Acanthosis nigricans
 Fungal infection

METABOLIC SYNDROME
- The metabolic syndrome (syndrome X, insulin resistance syndrome) consists of a constellation of metabolic
abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM)
- Major features of metabolic syndrome :
o Central obesity
o Hypertriglyceridemia
o Low HDL
o Hyperglycemia
o hypertension
- National Cholesterol Education Program and Adult Treatment Panel III (NCEP:ATPIII) criteria :

- Risk factors:
o Overweight / obesity
 KHUSUSNYA CENTRAL ADIPOSITY
o Sedentary lifestyle
 Increase adipose tissue (biasanya central adipose)
 Reduced HDL cholesterol
 Increase triglyceride
 High BP
 Increase glucose
o Aging
 Biasanya menyerang di usia lebih dri 50 tahun
o Diabetes Mellitus
 Hampir 75% dari penderita DM type 2 punya metabolic syndrome
o Coronary Heart Disease
o Lipodystrophy
 Genetic :
 Berardinelli Seip congenital lipodystrophy
 Dunnigan familial partial lipodystrophy
 Acquired
 HIV related lipodystrophy
- Etiology :
o Insulin resistance (most accepted)
 Insulin memiliki sifat antilipolysis dan secresi LPL (lipoprotein lipase) untuk memecah
triglyceride jadi FFA (tapi antilipolysis lebih dominan)
 Saat terjadi insulin resistance, increase lipolysis menghasilkan lebih banyak FFA  membuat
insulin resistance semakin parah dengan modifying downstream signalling
 FFA bisa mengganggu kerja insulin uptake sugar ke sel, membentuk triglyceride di skeletal
dan cardiac muscle, dan peningkatan produksi gula dan akumulasi triglyceride di liver
 Leptin Resistance
 Leptin berfungsi untuk decrease appetite, promote energy expenditure, increase
insulin sensitivity
 Leptin juga diproduksi dari adipocyte
 Saat obese, hyperleptinemia terjadi  resistance di hypothalamus dan jaringan2
lain  terjadi hyperlipidemia, hypertension, inflammation, insulin resistance,
atherosclerosis
o Increased waist circumference
 FAKTOR PALING UMUM SEKARANG
 Harus dibedakan antara central obesity:
 Fat di visceral : pemecahan FFA dibawa ke liver (berbahaya fatty liver)
 Fat di SubCutaneous : pemecahan FFA dibawa ke systemic dan tidak direct ke liver
 Untuk membedakan harus CT atau MRI
o Dyslipidemia
 Peningkatan FFA ke liver akan meningkatkan produksi VLDL (yang mengandung Apo B dan
triglyceride rich)
 Hypertriglyceridemia merupakan marker yang baik dari insulin resistance
 Reduction in HDL
 Terjadi karena perubahan komposisi dan metabolism
 Hypertriglyceridemia membuat HDL menurun karena berkurangnya cholesteryl ester
yang merupakan komposisi HDL
 HDL clearance juga bertambah cepat karena hypertriglyceride
 Hypertriglyceridemia juga membentuk small dense LDL yang atherogenic
o Glucose intolerance
 Defects in insulin action membuat glucose production liver meningkat dan reduced glucose
uptake di tissues
o Hypertension
 Di physiology normal, insulin memiliki efek vasodilatasi dan absorpsi Na di ginjal
 Ketika Insulin resistance, efek vasodilatasi berkurang, tapi absopsi Na tetap meningkat 
bisa terjadi hypertension
 Selain itu, insulin punya efek meningkatkan Sympathetic Nervous system  kalo diabet,
terjadi hyperinsulin  hyperactive of sympathetic nervous system  vasoconstriction
o Proinflammatory cytokines
 Peningkatan proinflammatory cytokines (IL-1, IL-6, IL-18, resistin, Tumor necrosis factor –
alpha (TNF-alpha), C-reactive protein (CRP)) membuat adipose tissue mass expands
o Adiponectin
 Pada metabolic syndrome terjadi pengurangan adiponectin (mekanisme blm jelas)
 Adiponectin produced exclusively by adipocytes
 Berguna untuk enhance insulin sensitivity, inhibit inflammatory process
 Inhibit glucose production di liver
 Enchance FFA oxidation dan glucose transport di muscle
- Clinical features :
o Sign and symptoms
 GAAD SYMPTOM KHAS
 PF ketemu waist circumference yang tinggi, dan hypertension
o Associated diseases
 Chronic Vascular Disease
 Dengan metabolic syndrome sekitar 1.5 – 3x lipat terkena CVD
 Type 2 DM
 Dengan metabolic syndrome bisa 3 – 5x lipat terkena DM type 2
o Other associated condition
 accompanied insulin resistance yaitu seperti increase ApoB and ApoCIII, uric acid,
prothrombic factors, serum viscocity, WBC count, Homocysteine, NAFLD, Hyperuricemia,
Polycystic Ovary syndrome, OSA.
- Diagnosis:
o Sesuai dengan tabel

o Ditambah dengan history taking ditemukannya : OSA, POS (polycystic ovary syndrome), family
history of CVD, DM
o PF : Waist circumference dan hypertension
o Lab test :
 Fasting lipid and glucose
 Additional measurement utk cek insulin resistance (Apo B, high sensitivity CRP, fibrinogen,
uric acid, urine microalbumin, liver function test)
o Sleep study kalo ada OSA
- Treatment
o Lifestyle  Diet (weight loss combined with exercise), Physical activity, Behavior modification,
Obesity
o LDL cholesterol (Statins, Ezetimibe, bile acids binding, restrict saturated fats diets)
o TAG (Fibrate  gemfibrozil or fenofibrate, Fish oil OMEGA3)
o HDL (Nicotinic Acid)
o BLOOD PRESSURE (ACEI or ARBs , sodium restriction)
o IMPAIRED FASTING GLUCOSE (aggressive glycemic control including metformin use)
o INSULIN RESISTANCE (biguanides and TZDs)
LIPID METABOLISM

- Lipoproteins (diurutin dari banyaknya fat dibanding proteins): chylomicron  vLDL  LDL  HDL (half
protein half lipid)
- Sources of fatty acid buat energy metabolism: dietary TAG, TAG hasil sintesis di liver, dan yang disimpan di
adipocytes as lipid droplets
o Small intestinal cell ada sodium glucose transporter (di apical side)  takes in 1 glucose molecule
dan 2 sodium molecule.  glucose di absorbed ke darah
o Dietary TAG arrived di usus halus as lipid droplets.  emulsify jadi micelle  TAG di degradasi by
lipase  fatty acid released dan di resintesis jadi TAG lagi
 TAG, cholesterol, apoproteins di packaged jadi chylomicrons  masuk ke darah 
lipoprotein lipase action release fatty acid  FA masuk ke hepatocyte  oxidized as fuel or
stored in TAG
 Oxidation of fatty acid terjadi di mitokondria. FA di transport ke darah as free fatty
acid (unesterified FA).
 FA di aktivasi sebelum di catabolized. Dengan ATP, enzim thiokinase (Acyl-CoA
synthetase) catalyzes (percepat reaksi) dari konversi FA ke active fatty acid (Acyl-
CoA) pake 1 ATP dan hasilin AMP dan PPi. Acyl-CoA synthetase ada di endoplasmic
reticulum, peroxixomes, dan inside and on the outer membrane of mitochondria.
 Acyl-CoA lanjut ke sistem beta-oxidation. 2 carbons at a time dipotong dari Acyl-CoA
molecules, starting at carboxyl end.  2 carbon units formed Acetyl-CoA  di
converts jadi cholesterol (pake enzim HMG-CoA reductase)
 Acetyl-CoA bisa di convert juga jadi malonyl-CoA to form fatty acids
  Glycolysis bisa hasilin glycerol juga yang kalo di combine sama 1 fatty acid jadi
monoacylglycerol. Kalo dicombine sama 3 fatty acid jadi triacylglycerol (triglyceride)
 TAG, apoprotein, dan phospholipid dipackage di golgi apparatus  lipoprotein.
 TAG transported from the intestines as chylomicrons dan from liver ke extrahepatic
tissues as vLDL. (contains only small amount of apo C dan E)
 TAG dari chylo sama vLDL di hidrolisis sama lipoprotein lipase (LL). LL butuh
phospholipid dan apo C-II, tapi apo A-II dan apo C-III inhibit kerja LL.  hidrolisis jadi
FFA dan glycerol
o vLDL lewatin lipase buat di liberate jadi IDL (intermediate density
lipoprotein)  diconvert jadi LDL (transport cholesterol to body tissue)
o kalo udah dipake LDL bakal return ke liver lewatin LDL receptor.  di
endocytosis  LDL bisa di recycled di golgi atau di buang lewat bile.
o sisa chylomicrons diambil liver lewat endocytosis (mediated by apo E via dua
apo E-dependent receptor)
o HDL synthesized and secreted from both the liver and intestine. Fungsi
utama HDL adalah sebagai tempat penyimpanan apo C and apo E yang
dibutuhkan untuk metabolisme dari chylomicrons and VLDL. The class B
scavenger receptor B1 (SR-B1) has been identified as an HDL receptor with a
dual role in HDL metabolism. Di cell liver dia fungsinya untuk fasilitasi HDL
anterin cholesteryl ester, sedangkan kalau dari extrahepatic cells dia anter
cholesterol and transport it back to the liver dengan tujuan eksresi oleh bile
acids (known as reverse cholesterol transport [RCT]). The second mechanism
yang berpengaruh terhadap RCT yaitu ada ATP-binding cassete transporters
A1 (ABCA1) and G1 (ABCG1).

Non-Alcoholic Fatty liver Disease

- Accumulation of fat di hepatocyte (berbeda dengan NASH yang ada efek inflammationnya)
- 1st type
o Karena raised level of FFA di plasma (karena mobilization dari adipose tissue atau hydrolysis dari
lipoprotein TAG oleh enzyme Lipoprotein Lipase dari extrahepatic tissue)
o Production of VLDL tidak seimbang dengan increasing FFA  TAG accumulate di liver jadi fatty liver
nd
- 2 type
o Karena metabolic block of production of plasma lipoproteins  accumulation TAG di liver
o Secara teori bisa karena :
 Block di Apolipoprotein synthesis
 block pada synthesis lipoprotein dari lipid dan apolipoprotein
 Kekurangan phospholipid yang berguna dalam pembuatan lipoprotein
 Failure in secretory mechanism
- Pathogenesis NAFLD are not entirely clear. Intinya triglyceride synthesis itu kelebihan daripada triglyceride
disposal, leading to accumulation of fat within hepatocytes. Obesity stimulates hepatocytes TAG
accumulation by altering the intestinal microbiota to enhance both energy harvest from dietary sources and
intestinal permeability. Reduced intestinal barrier function memperbolehkan hepatic exposure to gut-
derived products  stimulates liver cells secrete inflammatory mediators yang bisa turunin insulin sensitivity.
Obese adipokines juga secreted untuk menurunkan tissue insulin sensitivity. Insulin resistance promotes
hyperglycemia which drivs the pancreas to secrete more insulin  hyperinsulinemia occurs  promotes lipid
uptake, fat synthesis, and fat storage  hepatic triglyceride accumulation.
- TAG nya sendiri ga hepatotoxic, tapi yang precursornya (FA and glycerol) and metabolic products nya (ROS)
may damage hepatocytes and leading to hepatocyte lipotoxicity. Intinya nanti akan terjadi kematian dari
hepatosit-hepatosit dan ada usaha untuk regenerasi.