venous hydrostatic pressure (Pc-venule) helps to maintain a balance in fluid reabsorption that minimizes accumulation of interstitial fluids while still allowing for tissue perfusion:

under normal circumstances, the net venular flow is approximately -5 mmHg. however, if venous volume increases due to compensatory salt and fluid retention, Jv-venule slowly rises to counterbalance the Jv-ateriole threshold and venular reabsorption is lost at the capillaries. this threshold allows for a period of subacute increases in venous volume without interstitial fluid accumulation, and thus without edema.

when this threshold is met, net Jv=0 (since Jv-venule now matches Jv-ateriole) and the system decompensates. that is, the venous system now longer has reserve capacity to counter the absorption of fluid. the net loss of fluid results in edema.

the location of edema depends on the nature of the heart failure.

• left-sided heart failure results in pulmonary edema. edema from acute heart failure requires an immediate increase in Jv of about 10 mmHg. myocardial infarction or coronary ischemia can cause the transmission of left heart pressures backwards through the pulmonary veins to the pulmonary capillaries. sudden back-up of the left heart causes pulmonary edema.

• right sided heart failure results in peripheral edema. in the early phases of subacute heart failure, neurohormonal systems blunt the effect of decreased cardiac function:
  these mechanisms initially compensate enough to maintain appropriate blood pressure. however, the dual activation of the renin-angiotensin-aldosterone axis and antidiuretic hormone to increase preload has an unintended consequence of also increasing venous hydrostatic pressure.

  so, rather than an immediate backflow of blood volume from the heart backwards into the venous system, cor pulmonale results in an increase in systemic volume without the same equivalent increase in cardiac output. the increase in fluid volume has to go somewhere: the peripheral interstitium.

  clinically, edema will not set in until the decompensated state. eventually, the threshold is crossed and edema will appear in dependent positions, mediated by gravity. the ankles and feet often reflect the accumulation in interstitial fluid.

• cardiomyopathies result in simultaneous pulmonary and peripheral edema.

resources:

• UpToDate.com
• Pathophysiology of Heart Disease, 4th Edition, Lilly
• Textbook in Medical Physiology And Pathophysiology: Essentials and clinical problems, Copenhagen Medical Publishers  1999 – 2000
• Wikipedia.org

yumtastic

Type I AIPS

also known as candidiasis-hypoparathyroidism-Addison’s disease-syndrome, and autoimmune polyendocrine candidiadis ectodermal dystrophy (APECED).

it is an autosomal recessive disorder caused by a mutation in the AutoImmune Regulator AIRe gene. this gene is expressed mainly in the thymus. its protein product is a transcription factor that allows the thymus cells to express tissue-specific genes so that thymus cells can present “self” antigens, normally found outside of the thymus, to maturing T-cells. T-cells with T-cell receptors that react too strongly to both the MHC and the MHC-presented antigen undergo apoptosis, a process called negative selection. in this way, the thymus ensures a pool of T-cells that do not react against the body.

without AIRe, maturing T-cells never encounter extrathymal antigens, and thus are never “deleted” from the T-cell pool. when they circulate in the body later in life, they may react with self-tissue, causing a host of variable tissue-specific autoimmune disorders.

the signs include:

• candidiadis from mild immune deficiency in mucocutaneous areas, which are often susceptible to yeast colonization and infection
• hypoparathyroidism from autoimmune attack of the parathyroid, which can lead to hypocalcemic tetany
• Addison’s disease from formation of antibodies against 21-hydroxylase enzyme, which is normally found in the adrenal cortex (zona glomerulosa)
• later phases include hypothyroidism, hypogonadism, vitiligo, alopecia, malabsorption, pernicious anemia, chronic autoimmune hepatitis, and more!

Type II AIPS

this is known as Schmidt’s Syndrome. unlike Type I AIPS, this has not been linked to one gene, but could be the result of many different genetic differences in HLA regions.

the HLA region is an area used to generate allotype diversity expressed within MHC molecules. allotypes are differences in gene products that vary between individuals. there are 6 significant variable HLA regions (HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, HLA-DR). HLA-A, -B, and -C are associated with MHC I allotypes while HLA-DP, -DQ, and -DR are associated with MHC II allotypes. MHC I is expressed by all nucleated cells – so RBCs have none and platelets have few. MHC II is expressed by Professional Antigen Presenting Cells (macrophages, B-cells, and dendritic cells). there are numerous possible alleles per HLA (up to 50 in some cases), but each person can only get two – one on each chromosome. thus, each person can express up to 12 possible HLA regions.

there are also non-HLA regions that constitute MHC allotypes.

variable MHC allotypes cause changed antigen and TCR interactions. this may lead to decreased negative selection and enhanced positive selection that allows aberrant self-reacting T-cells into the T-cell pool. specific HLA haplotypes are related to specific tissue autoimmune disorders. DQ2 and DQ8 are associated with Schmidt’s syndrome. minor regions are thought to cause slow progressing autoimmune disorders.

signs include:

• Addison’s disease
• hypothyroidism from antibodies generated against thyroglobulin
• diabetes mellitus (type 1) from antibodies generated against glutamate dehydrogenase
• and others, including hypogonadism and vitiligo (the loss of melanocytes)

preeclampsia is a condition of new-onset hypertension, proteinuria, and edema most often appearing after 20 weeks of pregnancy.

pathogenesis is still poorly understood. existing literature favors preexisting maternal endothelial dysfunction that are triggered by pregnancy. observations that support this include:

• women with preexisting vascular disease are more susceptible
• high plasma fibronectin (involved in wound healing),  Factor VIII antigen, and thrombomodulin (coactivator of anticoagulant Protein C)
• impaired vasodilation (decrease flow-mediation, NO, prostacyclin) and increased vasoconstriction (high endothelins, thromboxanes)

some other possible etiologies include:

• immune rejection of the placenta
• compromised placental perfusion
  • incomplete cytotrophoblastic growth into the myometrial layer

pathophysiology is thought to involve an unregulated release of free thrombin occurs. this can proceed to DIC. a number of factors may cause this:

• an imbalance between circulatory VEGF and anti-VEGF (sFlt-1, sEng) factors shifts against angiogenesis
  
  • this could lead to inadequate vascularization of the placenta
  • could be a primary placental ischemia or secondary to other ischemic factors
• placental hypoperfusion due to abnormal uterine vasculature that is unable to accommodate the normal rise in blood flow to the fetus/placenta
  • this can lead to atherosis, fibrinoid necrosis, thrombosis, sclerotic narrowing of arterioles, and placental infarction
  • could be a primary placental ischemia or secondary to other ischemic factors

one unifying hypothesis:

HELPP

one variant of preeclampsia is HELPP, an abbreviation of:

• Hemolytic anemia
• Elevated Liver enzymes
• Low Platelet count

this condition involves preeclampsia with headache, malaise, edema, and right upper quadrant pain. HELPP often indicates that preeclampsia has triggered hepatic failure.

preeclamptic patients are already prone to spontaneous hemorrhages. the liver is thought to be particularly prone because fibrin split products can deposit in the reticuloendothelial system of the liver. multiple previous subclinical spontaneous hemorrhages within the small hepatic sinusoids and arterioles may go unnoticed symptomatically and leave the liver in a fragile state. fibrin thrombi may be left uncleared in the liver.

occasionally, a trigger (such as DIC) may cause extreme hypoperfusion of the liver, leading to infarction. periportal necrosis can coalesce and form a subcapsular hematoma with rupture of Glisson’s capsule. this results in intraperitoneal hemorrhage.

this progression is rare, but has a high mortality. right upper quadrant pain along with preeclamptic pain is a diagnostic hallmark for HELPP. however, it is best diagnosed with abdominal ultrasound. termination of pregnancy is considered the first step in treatment.

eclampsia

the patient may progress to full eclampsia, which is only defined by convulsions, and is often accompanied by seizures or coma. though preeclampsia often occurs prior to eclampsia, but no preeclamptic signs have to appear for eclamptic convulsion. the underlying pathophysiology is thought to be the same as preeclampsia with additional fulminant DIC triggering vasospasms and the convulsions.

general measures

• educate the family
• document occurrences on a calendar to evaluate effectiveness of treatments
• identify precipitating factors
• arrange for school professional to administer medicine if child is school-aged

abortive

• coping mechanisms: hot/cold shower, rest in a quiet, dark room with cool cloth applied to forehead
• serotonin agonists: triptans [sumatriptan]
  • activates 5-HT1b and 5-HT1d receptors, which inhibit release of vasodilatory peptides, promoting vasoconstriction
  • treats vasospasm
  • avoid concurrent use of SSRIs due to serotonin syndrome
• analgesic at onset: NSAIDs [ibuprofen, naproxen], acetaminophen
  • try to avoid chronic, daily use
  • watch out for rebound headaches that can be confused for migraines
• antiemetics if nauseous: D2 antagonists [metoclopramide, phenothiazines]
  • rectal administration is better tolerated than oral

prophylactic

• avoid triggers
• recommended if headache frequency > 4 times a month
• beta blockers: propanolol
  • risk of stroke
• anticonvulsants: valproic acid, topiramate, gabapentin, phenobarbital, phenytoin
  • increase GABA inhibition in cortex
• antidepressants: tricyclics [amitriptyline]
  • watch out for anticholinergic effects

malignant hypothermia is the unopposed consumption of ATP in muscles with excessive oxygen consumption. Ryanodine receptor is used as a bridge to communicate T-tubule depolarization to the sarcoplasmic reticulum, which has stored Ca++. depolarization triggers Ryanodine receptor to release stored Ca++, leading to cross-bridge cycling in the muscle cell and contraction.

in malignant hyperthermia, these receptors are defective and release excessive Ca++. the real kicker is that the excess Ca++ released needs to be reabsorbed – this requires alot of ATP. excess mitochondrial oxidative phosphorylation cycles occur to generate this, leading to heat generation (hyperthermia).

halogenated hydrocarbons bind to the Ryanodine receptor defect and expose this weakness. drugs that trigger this include:

• halothane
• isoflurane
• sevoflurane
• succinycholine (an exception, as it is not halogenated)

the antidote is dantrolene. this molecule binds to Ryanodine receptor and deactivates it.

these are a set of hemolytic anemias that affect small blood vessels. they include TTP, HUS, DIC, SLE, and malignant hypertension. these anemias are identified by a characteristic helmet-shaped schistocyte, which are fragments of red blood cells shredded by collision with abnormal fibrin-clot meshes within the microvasculature. these anemias are typical of small blood vessels with high shear stress.

disseminated intravascular coagulopathy

DIC represents an imbalance between coagulation and fibrin breakdown that results in excessive clots that deplete platelets, leading to increased bleeding. it is mediated by exposure of tissue factor (TF) to the vasculature, often the result of vascular damage. TF activates coagulation factors that initiate the extrinsic pathway of the clotting cascade. clots form and platelets are consumed. this leads to excess bleeding downstream.

in response, fibrinolysis begins to occur. clots are broken down, leading to fibrin degradation products (FDPs) that are themselves powerful anticoagulants. this further induces hemorrhage.

a variety of causes trigger DIC.

diagnosis is made through lab results.

clinically, DIC presents as shock:

• multiorgan failure (renal, pulmonary, neural, skin, GI)
• hypotension
• increased vascular permeability

thrombotic thrombocytopenic purpura

TTP is caused by decreased activity of ADAMTS-13, a matrix metalloprotease (MMP) that would normally cleave von-Willebrand Factor (vWF). defects include auto-antibodies against ADMTS13 (idiopathic TTP) and inherited defects (congenital TTP). without this enzyme, vWF can spontaneously activate the coagulation cascade.

this leads to platelet-fibrin clots that can quickly use up platelets to generate microthrombi that circulate in the vasculature. TTP-induced microthrombi cause shearing stress on the red blood cells, creating the characteristic schistocyte apperance on blood smear.

because TTP amplifies areas of normal vWF distribution, the microthrombi are normally generated in areas of high shear stress within microvasculature. TTP manifests as a clinical pentad:

• neurological: altered mental status, stroke, headaches
• anemia: anemia, jaundice, paleness
• renal: dark urine, low urine output
• thrombocytopenia: easy bruising, purpura
• fever

hemolytic uremic syndrome

HUS is a clinical diagnosis that emphasizes renal failure with or without neurological signs (ART):

• Anemia: anemia, jaundice
• Renal: dark urine
• Thrombocytopenia: easy bruising, purpura

it is commonly associated with childhood EHEC infections. 10% of EHEC infections cause HUS. EHEC is the most common cause of childhood acute renal failure.

think of it as a clinical subset of TTP. only ADAMTS13 deficiency separates TTP from HUS. because it is difficult to differentiate the two clinically, physicians may assess a patient with a combined diagnosis of TTP-HUS – especially in adults.