Diabetes Mellitus, DKA vs HHNS

Type 1 vs Type 2 Diabetes 

DKA vs HHNS

Energy Use During Exercise, Fasting

During Exercise

During Fasting 
Fasting (early, between meals)
glucagon-mediated, glycogen primary source 
- Liver glycogenolysis
       muscle glycogen can only be used as an energy source for muscle cells because muscle cells 
       lack glucose-6-phosphatase 
- Some gluconeogenesis
       fully activated after glycogen is depleted 

Starvation (1-3 days)
glycogen depleted, fatty acids major source 
- Liver gluconeogenesis
      from lactate + alanine, odd chain free fatty acids 
- Fatty acid oxidation 
      by muscle and liver 

Starvation (>3 days)
acetyl CoA accumulates, exceeds capacity of TCA cycle; ketone bodies and
protein major source
- Ketone bodies 
      ketones can be used by brain, heart, and skeletal muscle, but not by RBCs as these lack 
      mitochondria) 
- Protein degradation for gluconeogenesis 

Imaging Interstitial Lung Disease

CXR patterns of Interstitial Lung Disease - ddx 

Peripheral Reticular - netlike pattern 
(1) IPF
(2) connective tissue disease (RA, scleroderma, MCTD)
(3) pneumoconiosis (asbestosis)








Linear - kerly A, B lines 
(1) CHF
(2) lymphangitic carcinomatosis
(3) sarcoidosis
(4) pneumonia 






Nodular - numerous small opacities
(1) granulomatosis 
     (a) miliary TB, histo/coccidio/blastomycosis 
     (b) sarcoidosis
     (c) hypersensitivity pneumonitis
(2) pneumoconiosis (berylliosis, silicosis, talcosis)
(3) smoking related
     (a) langerhans cell histiocytosis 
     (b) respiratory bronchiolitis-associated interstitial lung disease,
          desquamative interstitial pneumonia
(4) malignant metastases




Cystic 
(1) end stage fibrosis due to sarcoidosis
(2) emphysema
(3) diffuse bronchiectasis (CF, ABPA, Kartagener's) 
(4) lymphangioleiomyomatosis (LAM)
(5) langerhans cell histiocytosis
(6) cystic PCP
(7) Birt-Hogg-Dubé syndrome

Alcohol-Induced Hypoglycemia

Ethanol is metabolized in the liver by NADH-producing oxidation reactions. Increase of the NADH/NAD+ ratio is responsible for hypoglycemia and hepatic fatty change following ethanol ingestion. Specifically, increased NADH/NADH+ ratio results in:

1. Decreased gluconeogenesis

2. Increased fatty acid synthesis, decreased fatty acid oxidation 

due to increased conversion of oxaloacetate to malate by malate dehydrogenase 

- excess NADH preferentially causes metabolism of oxaloacetate to malate, depleting 

oxaloacetate and hindering gluconeogenesis 

- excess NADH and acetyl-CoA stimulates fatty acid synthesis and inhibits fatty acid oxidation, 

leading to fatty acid accumulation

- fatty acids combine with glycerol 3-P  (also increased due to elevated NADH) to form 

triacylglycerols 

3. Lactic acidosis 

due to increased conversion of pyruvate to lactate by lactate dehydrogenase 

- pyruvate metabolism is preferably shunted to a lactate producing pathway that utilizes NADH, as opposed to entering the TCA cycle via conversion to acetyl-CoA which requires NAD+ 

- lactate is used for gluconeogenesis once EtOH is metabolized and NADH:NAD ratio normalizes; until then, excess lactate accumulates in serum 

Cushing's Syndrome, basics

Cushing's Syndrome = non-physiologic hypercortisolism from any cause

Pathophysiology

• ACTH-dependent
• Cushing’s disease: (2nd most common!) ACTH secreting pituitary adenoma causing bilateral adrenal hyperplasia
• Ectopic ACTH secretion: associated with malignancy, most commonly SCLC; also neuroendocrine thymic and pancreatic tumors
• Rare: ectopic CRH secretion
• ACTH-independent
• Iatrogenic: (most common!) 2/2 prescribed glucocorticoids - oral, topical, inhaled; also megestrol acetate and ritonavir
• Adrenocortical adenomas and carcinomas: primary adrenal cortisol hypersecretion
• Rare: primary adrenal familial forms, ectopic cortisol secretion

Clinical Presentation  - ROS: positive?

• Appearance: central obesity, moon facies, buffalo hump, striae, hyperpigmentation
• CV: HTN, VTE
• MS: proximal myopathy, osteoporosis
• Heme: easy bruising, immune suppression
• Endo: diabetes, hirsutism and menstrual irregularity in women
• Psych: depression, agitation/irritability, anxiety

Diagnosis

• Dexamethasone suppression test
• Exogenous steroid inhibits endogenous cortisol production via stimulation of negative feedback loop
• Low-dose, 1 mg: initial screening, tests integrity of negative feedback loop
• High-dose, 8 mg: localizes ACTH source
• CRH stimulation test
• Administer IV CRH, assess ACTH/cortisol levels
• Increased ACTH/cortisol levels with pituitary source vs no change with other etiologies
• Inferior petrosal sinus sampling (gold standard)
• Catheterize inferior petrosal veins, measure central:peripheral ATCH gradient after CRH administration
• Increased central:peripheral gradient suggests pituitary source vs no difference with ectopic source
• Serum ACTH, cortisol
• Imaging: pituitary MRI, chest/abd CT

Treatment 

• Iatrogenic: stop offending agent
• Cushing’s disease: transphenoidal surgery
• Other: medical tx (cabergoline, pasireotide), pituitary irradiation
• Ectopic ACTH secretion: remove tumor
• Nonresectable tumors: suppress cortisol synthesis with ketoconazole, metyrapone, etomidate
• Adrenalectomy: medical or surgical
• Primary adrenal disease: adrenalectomy

Approach to Primary Amenorrhea

In females, normal puberty begins between 8 - 12 years of age with the onset of breast development, or thelarche, followed by pubic hair growth, or pubarche.  

Menarche occurs between 2 - 3 years after thelarche. Primary amenorrhea is defined as the absence of menarche by 15 years of age in the presence of normal growth. Secondary amenorrhea is defined as the absence of menses for at least 6 months after onset of normal menarche. 

In order to occur, menarche requires: 

(a) the presence of a uterus

(b) a patent outflow tract

(c) proper functioning of the hypothalamic-pituitary-ovarian axis 

         - ie, GnRH pulsatility, LH/FSH release, and appropriate ovarian 

         response to circulating LH/FSH 

When approaching primary amenorrhea, it may be helpful to think in terms of the origins of primary and secondary sexual characteristics. 

An algorithm for working through differential diagnoses using this information is presented below. 

The pathway of male sexual differentiation is important to keep in mind when thinking through conditions where there is an inconsistency between the sex chromosomes and the sexual phenotype present.